Universal method for generating axial chirality and preparing axial chirality aromatic tertiary amine nitrogen-oxygen ligand compound through chiral associated strategy

Abstract

The invention belongs to the field of asymmetric catalysis and organic synthesis, and particularly provides a universal method for generating axial chirality through a chiral associated strategy, and the method is characterized in that a chiral aromatic tertiary amine compound of a nitrogen-free chiral center generates a new aromatic tertiary amine nitrogen-oxygen (NO) chiral center through intramolecular chiral oxidation induction; due to the structural rigidity of the chiral aromatic tertiary amine nitrogen oxide compound, when the steric hindrance of different substituent groups Rb and Rs connected with the ortho-position of an aromatic ring is relatively large, the rotation of the chiral aromatic tertiary amine nitrogen oxide compound is hindered, and a new rotation hindered axial chirality is generated along with the formation of an aromatic tertiary amine chiral nitrogen oxide center. Through the method and regulation of structures and functional characteristics of different substituent groups Rb and Rs, various types of axial chiral ligands, chiral small-molecule catalysts, medicine and pesticide intermediates and chiral synthons can be prepared; the method has important scientific and application values in design, synthesis and application of chiral ligands and chiral catalysts, especially ligands and catalysts containing axial chirality and chiral compounds with special functions.

Description

Technical Field

[0001] The invention belongs to the field of asymmetric catalysis and organic synthesis, and specifically relates to a general method for generating axial chirality and preparing axial chiral aromatic tertiary amine nitrogen oxide ligand compounds through a chiral companion strategy. Background Art

[0002] According to IUPAC rules, axial chirality refers to stereoisomerism formed by four groups arranged in a non-planar manner around a chiral axis. Axial chiral compounds include atropisomers, whose chirality originates from the steric effect of the substituents at both ends of the chemical bond, dipole-dipole interaction or other electrostatic interactions, thereby hindering the free rotation of the chemical bond and producing two isomers that cannot completely overlap and are mirror images of each other. Based on the energy required for mutual conversion between the two forms or the racemic half-life at 37°C, atropisomers are divided into three categories: Class I atropisomers include fast equilibrium rates (t 1 / 2 The atropisomers are atropisomers with a rotational energy barrier of less than 20 kcal / mol; Class II atropisomers have a moderate equilibrium rate (t 1 / 2 Units range from hours to days), which is applicable to compounds with atropisomer barriers between ΔErot≈20-30 kcal / mol; the equilibrium rate of type III atropisomers is very slow (t 1 / 2 In units of years, ΔErot>>20-30 kcal / mol), that is, there is virtually no interconversion. This class of compounds is very similar to conventional compounds with chiral stereocenters.

[0003] Axial chiral compounds exist in a large number of natural products, such as vancomycin, nephron, malinopyridine, gossypol and true polyphagin in natural products. In addition, there are many examples of atropischemia in active pharmaceutical ingredients (APIs) and agricultural products, chiral ligands and organic catalysts, functional materials such as liquid crystals, chiral switches, coolants and lubricants, and even molecular rotors. In the field of chemistry, especially in the field of asymmetric synthesis, axial chiral ligands such as BINAP, BINOL, BINAM, and axial chiral phosphoric acid catalysts have been discovered.

[0004]

[0005] In recent years, atropisomers have also evolved from classical structures consisting of only the same bi(hetero)aryl skeleton, such as C2-symmetric binaphthyl catalysts, to axial chiral skeletons with two different rings connected, and even to skeletons containing only one ring structure. Axial chiral compounds have become one of the most attractive ligands and basic advantage skeleton catalysts in asymmetric synthesis and catalysis due to their rigid, precise structure and stability. Therefore, the catalytic enantioselective synthesis of axial chiral skeletons has received increasing attention and has made significant progress. The currently established catalytic asymmetric synthesis methods mainly include center-axial chiral transformation, racemic or prochiral biaryl functionalization (desymmetry, kinetic decomposition), aryl-aryl coupling, direct arylation, cycloaddition synthesis methods, etc.

[0006] Over the past few decades, the chemical applications and development of tertiary amine nitroxide (NO) compounds have attracted increasing attention. Functional molecules with tertiary amine nitroxide (NO) structures are ubiquitous in nature. For example, trimethylamine-nitroxide (TMAO), a compound that may be associated with human cancer and cardiovascular disease, is also a fish protein stabilizer. In addition, many nitroxides are non-toxic derivatives of the corresponding amines and are common metabolites of drugs and natural products. Synthetic nitroxides are increasingly used in a variety of medical and health fields, with recent examples including magnetic resonance imaging agents, prodrugs, targeted cytotoxicity, and antibacterial drugs. In addition, oligomeric nitroxides have the potential to replace other hydrophilic oligomers and polymers, such as polyethylene glycol (PEG). Studies have shown that oligomeric nitroxides have good blood compatibility and can be used as invisible agents for drug or material surface attachment. The application of nitroxides in the biomedical field has developed rapidly due to their unique chemical properties. For example, the biological activity of botulinum toxin depends on the unique N+-O-bond and the resulting zwitterionic properties of nitroxides. In addition, they are also key ingredients for the preparation of various functionalized nitrogen-heterocycles, drugs and drug intermediates, as well as detergents, soaps, toothpastes, shampoos and cosmetics, and are also crucial for the design and development of drugs with unknown biological activities.

[0007] Nitrogen oxides have significant nucleophilicity and alkalinity, and can react with various molecules or metals to form complexes. The Lewis basic oxygen atom of nitrogen oxides acts as an electron pair donor and can form molecular adducts or complexes with Lewis acidic compounds. Similarly, chiral nitrogen oxides have important application value as ligands or catalysts in the field of asymmetric synthesis. However, the application of chiral nitrogen oxides in asymmetric catalytic reactions has not been developed until recent decades. In 1993, Ian.O'Neil et al. synthesized a series of chiral tertiary amine nitrogen oxides (as shown in Scheme 5a) by selectively oxidizing N-alkylated L-proline derivatives (O'Neil, IA; Miller, ND; Kalindjian, SB Synlett. 1993, 515-518.). Chiral tertiary amine nitrogen oxides have been shown to form hydrogen bonds and stable conformations with hydrogen atoms of adjacent amides in the molecule, thereby producing a stable chiral center on nitrogen. In 1997, they further developed similar tertiary amine nitrogen oxides derived from α,α-diphenylpyrrolidinemethanol (as shown in Scheme 5b) and used them as organocatalysts for the asymmetric catalysis of α-chloroacetone.

[0008]

[0009] Borane reduction reaction (O'Neil, IA; Turner, CD; Kalindjian, SB Synlett. 1997, 777-780.). In 1998, Nakajima et al. reported a class of axially chiral bipyridine N, N'-dioxides (as shown in Scheme 5c (S)-1) and bisquinoline N, N'-dioxides (as shown in Scheme 5c (S)-2) derived from BINOL with C2 symmetry. Bisquinoline N, N'-dioxide has been shown to be a good catalyst for the asymmetric addition of allyltrichlorosilane with aldehydes (Nakajima, M.; Saito, M.; Hashimoto, SB Am. Chem. Soc. 1998, 120, 6419-6420.).

[0010] Feng Xiaoming's group initially studied chiral nitroxides through asymmetric silylation reactions. In 2001, they studied the asymmetric Strecker reaction promoted by C2-symmetric bisquinoline N,N'-dioxides with mediocre results. Inspired by the bifunctional catalytic concept of Shibasaki's group, they developed prolineamide-based nitroxide (S)-1-titanium (IV) catalysts for asymmetric silylation of ketones with moderate enantioselectivity (Shen, Y.-C.; Feng, X.-M.; Zhang, G.-L.; Jiang, Y.-Z. Synlett. 2002, 1353-1355.). Based on these studies, they proposed the idea of ​​combining the key features of multidentate, bifunctional catalysts, and eventually synthesized a novel C2-symmetric proline-based N,N'-dioxide by connecting two nitroxide units with a variable linker as shown below.

[0011]

[0012] In 2006, Feng Xiaoming's group first applied their designed C2-symmetric N,N'-dioxide to titanium-catalyzed asymmetric silylation of ketones, with an ee value of up to 92% (Li, Q.-H.; Liu, X.-H.; Wang, J.; Shen, K.; Feng, X.-M. Tetrahedron Lett. 2006, 47, 4011–4014.). In 2007, Feng Xiaoming's group achieved a major breakthrough in N,N'-dioxide ligands in the study of adjustable enantioselective allylation catalyzed by N,N'-dioxide and its In(III) complex (Zhang, X.; Chen, D.-H.; Liu, X.-H.; Feng, X.-M. J Org. Chem. 2007, 72, 5227-5233.). So far, Feng Xiaoming's group has established a library of structurally diverse N,N'-dioxide ligands, including N,N'-dioxanes (D) with N-terminal linkers (AC) and carboxyl-terminal linkers. The linking units can be conformationally flexible alkyl chains (A and D) or rigid aromatic chains (B and C).

[0013]

[0014] In recent years, Liu Xiongli's team at Guizhou University has developed a series of rigid C2-symmetric chiral "Guizhou Eagle" catalysts based on the multi-dentate ligand chelation catalytic mechanism of the "eagle catching chicks" bionic model and using cheap and readily available amino acids as raw materials.

[0015]

[0016] It was successfully applied in the asymmetric catalytic Friedel-Crafts alkylation reaction of indole, and under mild conditions, a yield of up to 90% and an enantioselectivity of up to 99% were obtained for various substrates ((a) Chen, Z.-Y.; Liu, X.-L. New J. Chem., 2024, 48, 1688-1695. (b) Wang, Y.-H.; Liu, X.-L. Org. Chem. Front., 2024, 11, 1314-1321.). These results further demonstrate the application prospects of nitrogen oxide ligands in asymmetric catalysis.

[0017] In summary, there have been many reports on bi / pyridine chiral nitrogen oxides and Feng's fatty tertiary amine chiral nitrogen oxide ligands, and they have been proven to have very good application prospects in the field of asymmetric catalysis. However, there are no reports on chiral aromatic tertiary amine nitrogen oxides. From the structural point of view, aromatic tertiary amine nitrogen oxides are different from pyridine nitrogen oxides and fatty tertiary amine nitrogen oxides. Generally speaking, for aromatic tertiary amines, due to the conjugated delocalization of the N lone pair electrons of aromatic tertiary amines, aromatic tertiary amine nitrogen oxides are easier to prepare than fatty tertiary amine nitrogen oxides, and the nitrogen oxide (NO) dipole size is easier to control. At the same time, due to the diversity of the structure and source of aromatic tertiary amines, the regulation of electrons and steric hindrance is more flexible and diverse. Therefore, the preparation of aromatic tertiary amine nitrogen oxides, NO dipole regulation, and coordination ability are more flexible and diverse than pyridine nitrogen oxides and fatty tertiary amine nitrogen oxides, so that they may coordinate with more types of central metals, reduce the reaction catalytic energy barrier, and improve catalytic activity and selectivity. Summary of the invention

[0018] The first purpose of the present invention is to propose a new concept of "chiral association": a chiral aromatic tertiary amine compound without a nitrogen chiral center induces the generation of a new aromatic tertiary amine nitrogen oxide (NO) chiral center through intramolecular chiral oxidation. Due to the structural rigidity of the chiral aromatic tertiary amine nitrogen oxide compound, when the steric hindrance of different substituent groups Rb and Rs connected to the ortho position of the aromatic ring is large, its rotation is hindered, and a new rotationally hindered axial chirality is generated simultaneously with the formation of the aromatic tertiary amine chiral nitrogen oxide center.

[0019] The above concepts and principles are shown as follows Figure 6 shown.

[0020] By regulating the structure and functional properties of different substituent groups Rb and Rs, various types of axial chiral ligands and chiral small molecule catalysts can be prepared. Rb and Rs are functional groups with specific functions such as coordination bonds and hydrogen bonds, preferably Figure 1 The substituent groups, Rb and Rs, shown are different commonly used coordinating substituent groups.

[0021] The steric hindering group BG and the chiral source include but are not limited to Figure 2 The groups shown;

[0022] Figure 1-2 and Figure 6 In the formula, R* is a chiral source, Ar is a substituted or unsubstituted C6-C50 aryl, aryl, condensed aryl, substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 aralkyloxy, substituted or unsubstituted C7-C50 aralkylthiol, substituted or unsubstituted C7-C50 aromatic heterocyclic group, substituted or unsubstituted C7-C30 aromatic amine, aromatic heterocyclic group, etc., R, R a , R c , R d , R f , R p , R q , R u , R v , R 2a , R 2b , R 2c , R 2u , R 3a , R 3b , R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R45 , R 46 , R 47 , R 48 , R 49 , R 50 Each is independently selected from a hydrogen atom, a C1-C30 alkyl group, a C1-C30 silyl group, a C1-C30 haloalkyl group, a C2-C30 alkenyl group, a C2-C30 alkynyl group, a halogen, a hydroxyl group, an alkoxy group, an acyloxy group, a thiol group, a thioether group, a nitro group, a carbonyl group, a carboxyl group, an ester group, an amino group and a substituted amino group, an imino group, a cyano group, an amide group, a phosphoamido group, a sulfonamide group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group, and an electron-withdrawing or or an electron donating protecting group or an arbitrary substituent; it may also be selected from a substituted or unsubstituted C6-C50 aryl, a fused aryl, a substituted or unsubstituted C7-C50 aralkyl, a substituted or unsubstituted C7-C50 aralkyloxy, a substituted or unsubstituted C7-C50 aralkylthiol, a substituted or unsubstituted C7-C50 aromatic heterocyclic group, a substituted or unsubstituted C7-C30 aromatic amine, an aromatic heterocyclic group, a fused heterocyclic group, and a fused heterocyclic group.

[0023] The second purpose of the present invention is to synthesize a series of novel axially chiral aromatic tertiary amine nitrogen oxide ligand compounds based on the new concept of "chirality association": the aromatic substituent groups (Rb, Rs) connected to the nitrogen oxide simultaneously produce (associate) new axial chirality due to the hindered rotation of steric hindrance, and through the structural and functional regulation of the aromatic substituent groups (Rb, Rs) and the joint action with chiral nitrogen oxide (NO) compounds, aromatic tertiary amine nitrogen oxide (NO)-axially chiral compounds with diverse structures and functions can be obtained.

[0024] Specifically, the above-mentioned axial chiral aromatic tertiary amine nitrogen oxide ligand compound includes Figure 3 The compounds shown in the structural formula are for illustration only, including but not limited to all racemic compounds of relative or absolute configurations, all possible chiral isomers such as (R)- or (S)-isomer compounds, etc.

[0025] Figure 3 In the formula, Y is selected from H, O; X is selected from O, S; R2 is selected from H, OH, OR 2a NR g R h ; R c , R d , R f , R g , R h , R 2a , R 3a , R 3b , R 1 , R 4 , R5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 Each is independently selected from a hydrogen atom, a C1-C30 alkyl group, a C1-C30 silyl group, a C1-C30 haloalkyl group, a C2-C30 alkenyl group, a C2-C30 alkynyl group, a halogen, a hydroxyl group, an alkoxy group, an acyloxy group, a thiol group, a thioether group, a nitro group, a carbonyl group, a carboxyl group, an ester group, an amino group and a substituted amino group, an imino group, a cyano group, an amide group, a phosphoamido group, a sulfonamide group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group, and an electron-withdrawing or an electron-donating protecting group or an arbitrary substituent; and may also be selected from a substituted or unsubstituted C6-C50 aryl, a fused aryl, a substituted or unsubstituted C7-C50 aralkyl, a substituted or unsubstituted C7-C50 aralkyloxy, a substituted or unsubstituted C7-C50 aralkylthiol, a substituted or unsubstituted C7-C50 aromatic heterocyclic group, a substituted or unsubstituted C7-C30 aromatic amine group, an aromatic heterocyclic group, a fused heterocyclic group, and a fused heterocyclic group.

[0026] Representatively, the above-mentioned axial chiral aromatic tertiary amine nitrogen oxide ligand compounds include: (hydroxy) proline alcohol nitrogen oxide compounds, (hydroxy) proline ester nitrogen oxide compounds, (hydroxy) proline amide nitrogen oxide compounds, (hydroxy) proline aldehyde nitrogen oxide compounds, 2-pyrrolidine amine nitrogen oxide compounds, 2-pyrrolidine nitrile nitrogen oxide compounds, 2-pyrrolidine oxamide nitrogen oxide compounds, 2-pyrrolidine urea nitrogen oxide compounds, 2-pyrrolidine thiourea nitrogen oxide compounds, 2-pyrrolidine oxazoline nitrogen oxide compounds, 2-pyrrolidine imidazole nitrogen oxide compounds, 2-pyrrolidine triazole nitrogen oxide compounds, 2-pyrrolidine benzothiazole nitrogen oxide compounds, 2-pyrrolidine benzoxazole nitrogen oxide compounds, 2-pyrrolidine benzimidazole nitrogen oxide compounds, etc. These chiral compounds can be widely used as small molecule chiral catalysts, chiral ligands and drug active substances, etc.

[0027] In order to increase the types and uses of the target chiral compounds, the substituent Rb or Rs can be widely selected from different types of (chiral) ligands or their structural combinations, which can form a two-dentate or multi-dentate chiral ligand together with the chiral nitrogen oxide compound; the ligand includes but is not limited to the following commonly used ligand types: oxygen ligands, nitrogen ligands, sulfur ligands, double bond ligands, sulfoxide ligands, nitrile ligands, sulfonamides, phosphamides, amide ligands, ureas, thioureas, oxazoline ligands, imidazoline ligands, thiazoline ligands, pyrazoles, triazoles, tetrazoles, pyrazoline, pyrroles, indoles and other heterocyclic ligands ( Figure 7).

[0028] Figure 7 Medium R*, R a , R c , R d , R f , R 21 , R 23 , R 24 , R 25 , R 26a , R 27a , R 30 , R 31 , R 35 , R 36 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 50 , R 51 , R 52 Each is independently selected from a hydrogen atom, a C1-C30 alkyl group, a C1-C30 silyl group, a C1-C30 haloalkyl group, a C2-C30 alkenyl group, a C2-C30 alkynyl group, a halogen (F, Cl, Br, I), a hydroxyl group, an alkoxy group, an acyloxy group, a mercapto group, a thioether group, a nitro group, a carbonyl group, a carboxyl group, an ester group, an amino group and a substituted amino group, an imino group, a cyano group, an amide group, a phosphoamido group, a sulfonamide group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group, and an electron-withdrawing or electron-donating protecting group or an arbitrary substituent group having a chain length of C1-C30; it can also be selected from a substituted or unsubstituted C6-C50 aromatic The invention can be any of a substituted or unsubstituted C7-C50 aralkyl group, a substituted or unsubstituted C7-C50 aralkyloxy group, a substituted or unsubstituted C7-C50 aralkylthiol group, a substituted or unsubstituted C7-C50 aromatic heterocyclic group, a substituted or unsubstituted C7-C30 aromatic amine group, any aromatic heterocyclic group (such as thienyl, benzothienyl, fluorenyl, furanyl, benzofuranyl, benzopyrrolyl, pyridyl, quinolyl, benzoquinolyl, etc.), a substituted heterocyclic group, a fused heterocyclic group (such as tetrahydroquinolyl, dihydroindole, dihydropyranyl, etc.), etc.

[0029] Different nitrogen oxide (NO) chiral sources can be combined with different ligands (represented by Rb, Rs) to obtain more types and chiral functional compounds with different functions. Representative axial chiral aromatic tertiary amine nitrogen oxide ligand compounds include but are not limited to: o-(p-methylbenzenesulfonamide) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(methylsulfonamide) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(p-nitrobenzenesulfonamide) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(carbonitrile) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(benzaldehyde) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(olefin) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(ester) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(amide) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(urea) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(thiourea) ) diphenyl (hydroxy) prolinol nitrogen oxides, o-(oxazoline) diphenyl (hydroxy) prolinol nitrogen oxides, o-(imidazole) diphenyl (hydroxy) prolinol nitrogen oxides, o-(benzimidazole) diphenyl (hydroxy) prolinol nitrogen oxides, o-(thiazole) diphenyl (hydroxy) prolinol nitrogen oxides, o-(benzothiazole) diphenyl (hydroxy) prolinol nitrogen oxides, o-(triazole) diphenyl (hydroxy) prolinol nitrogen oxides, o-(tetrazolyl) diphenyl (hydroxy) prolinol nitrogen oxides, o-(p-methylbenzenesulfonamide) (hydroxy) prolinamide nitrogen oxides, o-(methylsulfonamide) (hydroxy) prolinamide nitrogen oxides, o-(p-nitrobenzenesulfonamide) ( hydroxy) prolineamide nitrogen oxides, o-(carbonitrile) (hydroxy) prolineamide nitrogen oxides, o-(benzaldehyde) (hydroxy) prolineamide nitrogen oxides, o-(olefin) (hydroxy) prolineamide nitrogen oxides, o-(ester) (hydroxy) prolineamide nitrogen oxides, o-(amide) (hydroxy) prolineamide nitrogen oxides, o-(urea) (hydroxy) prolineamide nitrogen oxides, o-(thiourea) (hydroxy) prolineamide nitrogen oxides, o-(oxazoline) (hydroxy) prolineamide nitrogen oxides, o-(imidazole) (hydroxy) prolineamide nitrogen oxides, o-(benzimidazole) (hydroxy) prolineamide nitrogen oxides, o-(thiazole) (hydroxy) prolineamide nitrogen oxides, o-(benzene) and thiazoles (hydroxy) proline amide nitrogen oxides, o-(triazoles) (hydroxy) proline amide nitrogen oxides, o-(tetrazolyls) (hydroxy) proline amide nitrogen oxides, o-(p-methylbenzenesulfonamide) (hydroxy) proline oxazoline nitrogen oxides, o-(methylsulfonamide) (hydroxy) proline oxazoline nitrogen oxides, o-(p-nitrobenzenesulfonamide) (hydroxy) proline oxazoline nitrogen oxides, o-(carbonitrile) (hydroxy) proline oxazoline nitrogen oxides, o-(benzaldehyde) (hydroxy) proline oxazoline nitrogen oxides, o-(olefins) (hydroxy) proline oxazoline nitrogen oxides, o-(esters) (hydroxy) proline oxazoline nitrogen oxides, o-(amides) (hydroxy) proline oxazoline nitrogen oxides,o-(urea) (hydroxy) prolyl oxazoline nitrogen oxide compounds, o-(thiourea) (hydroxy) prolyl oxazoline nitrogen oxide compounds, o-(oxazoline) (hydroxy) prolyl oxazoline nitrogen oxide compounds, o-(imidazole) (hydroxy) prolyl oxazoline nitrogen oxide compounds, o-(benzimidazole) (hydroxy) prolyl oxazoline nitrogen oxide compounds, o-(thiazole) (hydroxy) prolyl oxazoline nitrogen oxide compounds, o-(benzothiazole) (hydroxy) prolyl oxazoline nitrogen oxide compounds, o-(triazole) (hydroxy) prolyl oxazoline nitrogen oxide compounds, o-(tetrazolyl) (hydroxy) prolyl oxazoline nitrogen oxide compounds. 、

[0030] Specifically, the above-mentioned axial chiral aromatic tertiary amine nitrogen oxide ligand compound includes Figures 4a-4d The compound shown in the formula, wherein R c , R d , R f , R 1 , R 2 , R 4 , R 5 , R 6 , R 7a , R 8a , R 11 , R 12 , R 13 , R 14 , R 21 , R 22 , R 23 , R 24 , R 25 , R 28a , R 29a , R 33 , R 34 , R 35 , R 36 , R 37 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48Each is independently selected from a hydrogen atom, a C1-C30 alkyl group, a C1-C30 silyl group, a C1-C30 haloalkyl group, a C2-C30 alkenyl group, a C2-C30 alkynyl group, a halogen, a hydroxyl group, an alkoxy group, an acyloxy group, a thiol group, a thioether group, a nitro group, a carbonyl group, a carboxyl group, an ester group, an amino group and a substituted amino group, an imino group, a cyano group, an amide group, a phosphoamido group, a sulfonamide group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group, and an electron-withdrawing or an electron-donating protecting group or an arbitrary substituent; and may also be selected from a substituted or unsubstituted C6-C50 aryl, a fused aryl, a substituted or unsubstituted C7-C50 aralkyl, a substituted or unsubstituted C7-C50 aralkyloxy, a substituted or unsubstituted C7-C50 aralkylthiol, a substituted or unsubstituted C7-C50 aromatic heterocyclic group, a substituted or unsubstituted C7-C30 aromatic amine group, an aromatic heterocyclic group, a fused heterocyclic group, and a fused heterocyclic group.

[0031] Specifically, the above-mentioned axial chiral aromatic tertiary amine nitrogen oxide ligand compound includes Figures 5a-5f The compounds shown have the potential to be small molecule chiral catalysts and chiral ligands, and can catalyze different types of asymmetric reactions alone or after coordination with metals. 2u , R 2c , R 3c , R 5 , R 6 , R 7a , R 8a , R 14 , R 36 , R 37 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50Each is independently selected from a hydrogen atom, a C1-C30 alkyl group, a C1-C30 silyl group, a C1-C30 haloalkyl group, a C2-C30 alkenyl group, a C2-C30 alkynyl group, a halogen, a hydroxyl group, an alkoxy group, an acyloxy group, a thiol group, a thioether group, a nitro group, a carbonyl group, a carboxyl group, an ester group, an amino group and a substituted amino group, an imino group, a cyano group, an amide group, a phosphoamido group, a sulfonamide group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group, and an electron-withdrawing or an electron-donating protecting group or an arbitrary substituent; and may also be selected from a substituted or unsubstituted C6-C50 aryl, a fused aryl, a substituted or unsubstituted C7-C50 aralkyl, a substituted or unsubstituted C7-C50 aralkyloxy, a substituted or unsubstituted C7-C50 aralkylthiol, a substituted or unsubstituted C7-C50 aromatic heterocyclic group, a substituted or unsubstituted C7-C30 aromatic amine group, an aromatic heterocyclic group, a fused heterocyclic group, and a fused heterocyclic group.

[0032] The third purpose of the present invention is to provide applications of these novel axially chiral aromatic tertiary amine nitrogen oxide ligand compounds in multiple fields such as small molecule catalysis, asymmetric metal catalysis, chiral medicines, pesticides, and chiral optoelectronic materials.

[0033] Specifically, the axially chiral aromatic tertiary amine nitrogen oxide ligand compound can be used as a new Lewis base or chiral organic small molecule catalyst to catalyze organic reactions or asymmetric organic reactions; as a metal ligand, it can form a chiral catalyst to participate in asymmetric reactions catalyzed by various metal catalysts or chiral metal catalysts; as an organic synthon or a chiral organic synthon to synthesize new catalysts or chiral catalysts; as a synthon to synthesize new phase transfer catalysts or chiral phase transfer catalysts.

[0034] The axial chiral aromatic tertiary amine nitrogen-oxygen ligand compound provided by the invention can be used for preparing electro-, photo-, magneto-, acid- and alkali-induced photoelectric materials.

[0035] The axially chiral aromatic tertiary amine nitrogen oxide ligand compound provided by the present invention can also be used to synthesize fluorescent materials, such as fluorescent probes, and can also be used to prepare trace metal detection reagents, dyes, fine chemical raw materials or medicines, pesticides and their intermediates or biologically active compounds.

[0036] The fourth object of the present invention is to provide a method for synthesizing a representative o-aryl chiral diamine compound, the synthesis route of which is as follows: Figure 8 shown.

[0037] The reaction steps are as follows:

[0038] (1) Using o-fluoronitrobenzene as the starting material, under the action of temperature T1, solvent S1, and base B1, a chiral prolinol compound C1 is reacted with the chiral prolinol compound C1 to form a S-type prolinol. N Ar 2Reaction, followed by nitro reduction, to form an ortho-aryl chiral diamine compound shown in formula II;

[0039] The solvent S1 includes one or more of alcohol, halogenated hydrocarbon and ether solvents; the base B1 includes one or more of inorganic base and organic base; the reaction temperature T1 is 25°C to 100°C;

[0040] (2) Under the conditions of temperature T4, solvent S4 and oxidant O1, the target axial chiral aromatic tertiary amine nitrogen-oxygen ligand compound represented by formula I is obtained by selective nitrogen oxidation of the chiral tertiary amine;

[0041] The oxidant O1 includes meta-chloroperbenzoic acid, peracetic acid, peroxyacetic acid, hydrogen peroxide, and ruthenium trichloride; the solvent S4 includes one or more of halogenated hydrocarbons, ethers, and nitrile solvents; and the reaction temperature T4 is -78°C to 20°C.

[0042] The raw materials o-fluoronitrobenzene and various chiral secondary amine compounds used in this method have the advantages of being easily commercially available, low cost, and thermally stable; the synthesis steps and reaction processes do not involve chiral centers, so through the configuration and purity control of chiral raw materials, it is easy to obtain target chiral o-aryl diamine compounds (II) with a defined structure, controllable chiral purity, and structural diversity and functional diversity. It can be widely used in the fields of organic catalysis, optoelectronic materials, etc.

[0043] After the ortho-aryl chiral diamine compound (II) is derived by amino substitution, alkylation, acylation, sulfonylation, phosphonylation, etc., a suitable oxidant is further selected to selectively oxidize the chiral tertiary amine to obtain the target chiral nitrogen oxide (NO) compound (I), accompanied by an axial chirality. This type of new chiral aromatic nitrogen oxide compound with axial chirality has a stable structure, simple preparation steps, high optical purity and good coordination ability, can form complexes with a variety of metal ions, form chiral catalysts to participate in asymmetric catalytic reactions catalyzed by various (chiral) metal catalysts, and act as a chiral Lewis base and organic small molecule catalyst to catalyze various asymmetric reactions. It has special photoelectric properties and good application potential.

[0044] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0045] 1. A new concept of "chiral association" is proposed, which has important scientific and application value for the design, synthesis and application of chiral ligands, chiral catalysts, especially ligands and catalysts containing axial chirality, and chiral compounds with special functions.

[0046] 2. The method for constructing a nitrogen-oxidized chiral center and simultaneously generating a hindered axial chiral center by nitrogen-oxidizing a chiral aromatic tertiary amine provided by the present invention, as well as a representative preparation method of an ortho-aryl chiral diamine compound, is particularly suitable for preparing an ortho-aryl chiral diamine compound with a large sterically hindered secondary amine. When the steric hindrance of the ortho-position group of the benzene ring is relatively large, the target compound will produce axial chirality. In addition, the target product is also an intermediate and chiral synthon for preparing multidentate (chiral) ligand compounds and electron transfer materials, and has important scientific and application value for the design, synthesis and application of chiral ligands, chiral catalysts, especially ligands and catalysts containing axial chirality and chiral compounds with special functions.

[0047] 3. The axially chiral aromatic tertiary amine nitrogen oxide ligand compound synthesized based on the new concept of "chiral association" provided by the present invention can be widely used as a new type of Lewis base or small molecule chiral catalyst and chiral ligand through the structural and functional regulation of the aromatic substituent groups (Rb, Rs) adjacent to the nitrogen oxide chiral center and the joint action with the chiral nitrogen oxide (NO) compound, and has potential scientific and application value in chiral science such as asymmetric catalysis, chiral synthesis, chiral resolution, and chiral substances.

[0048] 4. The axially chiral aromatic tertiary amine nitrogen oxide ligand compound provided by the present invention has an o-phenylenediamine structural unit, high optical purity and good coordination ability, can form complexes with a variety of metal ions, is a good (chiral) metal ligand and catalyst, has special photoelectric properties, and has good application potential.

[0049] 5. The axially chiral aromatic tertiary amine nitrogen oxide ligand compound provided by the present invention can be widely used in the fields of chiral medicines, pesticides and chiral materials due to its structural diversity, functional groups and types. It can also be used as a (chiral) metal ligand to form a chiral catalyst to participate in various asymmetric organic reactions catalyzed by (chiral) metal catalysts, and as a chiral Lewis base and chiral organic small molecule catalyst to catalyze various asymmetric organic reactions.

[0050] 6. The preparation method of the axial chiral aromatic tertiary amine nitrogen oxide ligand compound provided by the present invention has a short synthetic route, simple operation steps, and is easy to separate and purify. Through the configuration and purity control of commercially available, low-cost, thermally stable o-fluoronitrobenzene and various types of chiral secondary amine compounds, it is easy to obtain structurally diverse o-aryl chiral diamine compounds with a defined structure and controllable chiral purity. After derivatization and transformation, the target axial chiral aromatic nitrogen oxide (NO) compound can be further obtained by selectively oxidizing the tertiary amine nitrogen.

[0051] The present invention will be further described in detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1Schematic diagram of Rb and Rs substituent groups in one embodiment provided by the present invention.

[0053] Figure 2 It is a schematic diagram of the steric hindering group BG in one embodiment provided by the present invention.

[0054] Figure 3 It is a schematic diagram of a representative axially chiral aromatic tertiary amine nitrogen oxide ligand compound in an embodiment provided by the present invention.

[0055] Figures 4a-4d It is a schematic diagram of a representative axially chiral aromatic tertiary amine nitrogen oxide ligand compound in another embodiment provided by the present invention.

[0056] Figures 5a-5f It is a schematic diagram of a representative axially chiral aromatic tertiary amine nitrogen oxide ligand compound in another embodiment provided by the present invention.

[0057] Figure 6 It is a schematic diagram of the principle of the general method for generating axial chirality through the chiral association strategy provided by the present invention.

[0058] Figure 7 Schematic diagram of a representative ligand structure provided by the present invention.

[0059] Figure 8 The invention provides a synthetic route for an axially chiral aromatic tertiary amine nitrogen-oxygen ligand compound (I) and an intermediate ortho-aryl chiral diamine compound (II).

[0060] Fig. 9 It is a schematic diagram of preparing an o-aryl chiral diamine compound (II) by nitro reduction provided by the present invention.

[0061] Fig.10 The present invention provides a schematic diagram of an oxidation preparation method of an axially chiral aromatic tertiary amine nitrogen oxide ligand compound (I).

[0062] Fig.11 It is a representative structural compound in an embodiment provided by the present invention.

[0063] Fig.12 It is a schematic diagram of the structure of the compound in a specific embodiment of the present invention.

[0064] Fig.13 It is the synthesis route diagram in Example 1 of the present invention. DETAILED DESCRIPTION

[0065] The technical scheme in the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Although the representative embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that various modifications and changes can be made to the present invention without departing from the scope of the present invention. Therefore, the scope of the present invention should not be limited to the embodiments, but should be limited by the attached claims and their equivalents.

[0066] The present invention provides a general method for generating axial chirality through a chiral association strategy, comprising: a chiral aromatic tertiary amine compound without a nitrogen chiral center is induced to generate a new aromatic tertiary amine nitrogen oxide (NO) chiral center through intramolecular chiral oxidation; due to the structural rigidity of the chiral aromatic tertiary amine nitrogen oxide compound, when the steric hindrance of different substituent groups Rb and Rs connected to the ortho position of the aromatic ring is large, its rotation is hindered, and a new rotationally hindered axial chirality is generated simultaneously with the formation of the aromatic tertiary amine chiral nitrogen oxide center.

[0067] Features and concepts such as Figure 6 As shown, wherein Rb and Rs are different commonly used coordination substituent groups, including but not limited to Figure 1 The substituent groups shown;

[0068] The steric hindering group BG and the chiral source include but are not limited to Figure 2 The groups shown;

[0069] Figure 1-2 and Figure 6 In the formula, R* is a chiral source, Ar is a substituted or unsubstituted C6-C50 aryl, aryl, condensed aryl, substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 aralkyloxy, substituted or unsubstituted C7-C50 aralkylthiol, substituted or unsubstituted C7-C50 aromatic heterocyclic group, substituted or unsubstituted C7-C30 aromatic amine, aromatic heterocyclic group, etc., R, R a , R c , R d , R f , R p , R q , R u , R v , R 2a , R 2b , R 2c , R 2u , R 3a , R 3b , R 1 , R 4 , R 5 , R 6 , R 7 , R8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 Each is independently selected from a hydrogen atom, a C1-C30 alkyl group, a C1-C30 silyl group, a C1-C30 haloalkyl group, a C2-C30 alkenyl group, a C2-C30 alkynyl group, a halogen (F, Cl, Br, I), a hydroxyl group, an alkoxy group, an acyloxy group, a mercapto group, a thioether group, a nitro group, a carbonyl group, a carboxyl group, an ester group, an amino group and a substituted amino group, an imino group, a cyano group, an amide group, a phosphoamido group, a sulfonamide group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group, and an electron-withdrawing or electron-donating protecting group or an arbitrary substituent group having a chain length of C1-C30; it can also be selected from a substituted or unsubstituted C6-C50 aromatic The invention can be any of a substituted or unsubstituted C7-C50 aralkyl group, a substituted or unsubstituted C7-C50 aralkyloxy group, a substituted or unsubstituted C7-C50 aralkylthiol group, a substituted or unsubstituted C7-C50 aromatic heterocyclic group, a substituted or unsubstituted C7-C30 aromatic amine group, any aromatic heterocyclic group (such as thienyl, benzothienyl, fluorenyl, furanyl, benzofuranyl, benzopyrrolyl, pyridyl, quinolyl, benzoquinolyl, etc.), a substituted heterocyclic group, a fused heterocyclic group (such as tetrahydroquinolyl, dihydroindole, dihydropyranyl, etc.), etc.

[0070] refer to Figure 6 Chiral aromatic tertiary amine compounds without tertiary amine nitrogen chiral centers induce the generation of new nitrogen oxide (NO) chiral centers through intramolecular chiral oxidation. Along with the generation of the nitrogen oxide (NO) chiral center, different aromatic substituent groups (Rb, Rs) connected to the nitrogen oxide simultaneously generate (accompany) new axial chirality due to steric hindrance. A nitrogen oxide (NO) chiral center can be constructed through a single chiral oxidation and a single ring axial chirality can be simultaneously generated. This provides a new idea, strategy and method for the precise and efficient synthesis of novel aromatic axial chiral nitrogen oxide (NO) compounds with diverse structures and functions. Through the structural and functional regulation of the aromatic substituent groups (Rb, Rs) adjacent to the nitrogen oxide chiral center and the joint action with the chiral nitrogen oxide (NO) compounds, these new structural axial chiral compounds can be widely used in small molecule catalysis, asymmetric metal catalysis, chiral medicine, pesticides and chiral optoelectronic materials.

[0071] Based on the above method, the present invention provides a class of Figure 3 The novel chiral aromatic nitrogen oxide compound with axial chirality shown in the figure is for illustration only, and includes but is not limited to all racemic compounds of relative or absolute configurations, all possible chiral isomers such as (R)- or (S)-isomer compounds, etc.

[0072] Figure 3 In the formula, Y is selected from H and O; X is selected from O and S; R 2 Selected from H, OH, OR 2a NR g R h ; R c , R d , R f , R g , R h , R 2a , R 3a , R 3b , R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14Each is independently selected from a hydrogen atom, a C1-C30 alkyl group, a C1-C30 silyl group, a C1-C30 haloalkyl group, a C2-C30 alkenyl group, a C2-C30 alkynyl group, a halogen (F, Cl, Br, I), a hydroxyl group, an alkoxy group, an acyloxy group, a mercapto group, a thioether group, a nitro group, a carbonyl group, a carboxyl group, an ester group, an amino group and a substituted amino group, an imino group, a cyano group, an amide group, a phosphoamido group, a sulfonamide group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group, and an electron-withdrawing or electron-donating protecting group or an arbitrary substituent group having a chain length of C1-C30; it can also be selected from a substituted or unsubstituted C6-C50 aromatic The invention can be any of a substituted or unsubstituted C7-C50 aralkyl group, a substituted or unsubstituted C7-C50 aralkyloxy group, a substituted or unsubstituted C7-C50 aralkylthiol group, a substituted or unsubstituted C7-C50 aromatic heterocyclic group, a substituted or unsubstituted C7-C30 aromatic amine group, any aromatic heterocyclic group (such as thienyl, benzothienyl, fluorenyl, furanyl, benzofuranyl, benzopyrrolyl, pyridyl, quinolyl, benzoquinolyl, etc.), a substituted heterocyclic group, a fused heterocyclic group (such as tetrahydroquinolyl, dihydroindole, dihydropyranyl, etc.), etc.

[0073] Representatively, axial chiral aromatic tertiary amine nitrogen oxide ligand compounds include, but are not limited to: (hydroxy) proline alcohol nitrogen oxide compounds, (hydroxy) proline ester nitrogen oxide compounds, (hydroxy) proline amide nitrogen oxide compounds, (hydroxy) proline aldehyde nitrogen oxide compounds, 2-pyrrolidine amine nitrogen oxide compounds, 2-pyrrolidine nitrile nitrogen oxide compounds, 2-pyrrolidine oxamide nitrogen oxide compounds, 2-pyrrolidine urea nitrogen oxide compounds, 2-pyrrolidine thiourea nitrogen oxide compounds, 2-pyrrolidine oxazoline nitrogen oxide compounds, 2-pyrrolidine imidazole nitrogen oxide compounds, 2-pyrrolidine triazole nitrogen oxide compounds, 2-pyrrolidine benzothiazole nitrogen oxide compounds, 2-pyrrolidine benzoxazole nitrogen oxide compounds, 2-pyrrolidine benzimidazole nitrogen oxide compounds. These chiral compounds can be widely used as small molecule chiral catalysts, chiral ligands and drug active substances.

[0074] In order to increase the types and uses of target chiral compounds, the substituent R b or R s The ligands may be widely selected from different types of (chiral) ligands or their structural combinations, which together with the chiral nitrogen oxide compound may form a bidentate or multidentate chiral ligand. These ligands may be selected from, but are not limited to, the following commonly used ligand types, such as oxygen ligands, nitrogen ligands, sulfur ligands, double bond ligands, sulfoxide ligands, nitrile ligands, sulfonamides, phosphamides, amide ligands, ureas, thioureas, oxazoline ligands, imidazoline ligands, thiazoline ligands, pyrazoles, triazoles, tetrazoles, pyrazoline, pyrroles, indoles and other heterocyclic ligands, etc. ( Figure 7 ).

[0075] Figure 7 Medium R*, R a , R c , R d , R f , R 21 , R 23 , R 24 , R 25 , R 26a , R 27a , R 30 , R 31 , R 35 , R 36 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 50 , R 51 , R 52 Each is independently selected from a hydrogen atom, a C1-C30 alkyl group, a C1-C30 silyl group, a C1-C30 haloalkyl group, a C2-C30 alkenyl group, a C2-C30 alkynyl group, a halogen (F, Cl, Br, I), a hydroxyl group, an alkoxy group, an acyloxy group, a mercapto group, a thioether group, a nitro group, a carbonyl group, a carboxyl group, an ester group, an amino group and a substituted amino group, an imino group, a cyano group, an amide group, a phosphoamido group, a sulfonamide group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group, and an electron-withdrawing or electron-donating protecting group or an arbitrary substituent group having a chain length of C1-C30; it can also be selected from a substituted or unsubstituted C6-C50 aromatic The invention can be any of a substituted or unsubstituted C7-C50 aralkyl group, a substituted or unsubstituted C7-C50 aralkyloxy group, a substituted or unsubstituted C7-C50 aralkylthiol group, a substituted or unsubstituted C7-C50 aromatic heterocyclic group, a substituted or unsubstituted C7-C30 aromatic amine group, any aromatic heterocyclic group (such as thienyl, benzothienyl, fluorenyl, furanyl, benzofuranyl, benzopyrrolyl, pyridyl, quinolyl, benzoquinolyl, etc.), a substituted heterocyclic group, a fused heterocyclic group (such as tetrahydroquinolyl, dihydroindole, dihydropyranyl, etc.), etc.

[0076] Different chiral nitrogen oxide (NO) sources can be combined with different ligands (represented by Rb, Rs) to obtain more types of chiral functional compounds with different functions. Representatively, these chiral nitrogen oxide (NO) compounds include but are not limited to: o-(p-methylbenzenesulfonamide) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(methylsulfonamide) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(p-nitrobenzenesulfonamide) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(carbonitrile) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(benzaldehyde) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(olefin) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(ester) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(amide) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(urea) diphenyl (hydroxy) prolinol nitrogen oxide compounds, o-(thiourea) Diphenyl (hydroxy) prolinol nitrogen oxides, o-(oxazoline) diphenyl (hydroxy) prolinol nitrogen oxides, o-(imidazole) diphenyl (hydroxy) prolinol nitrogen oxides, o-(benzimidazole) diphenyl (hydroxy) prolinol nitrogen oxides, o-(thiazole) diphenyl (hydroxy) prolinol nitrogen oxides, o-(benzothiazole) diphenyl (hydroxy) prolinol nitrogen oxides, o-(triazole) diphenyl (hydroxy) prolinol nitrogen oxides, o-(tetrazolyl) diphenyl (hydroxy) prolinol nitrogen oxides, o-(p-methylbenzenesulfonamide) (hydroxy) prolinamide nitrogen oxides, o-(methylsulfonamide) (hydroxy) prolinamide nitrogen oxides, o-(p-nitrobenzenesulfonamide) (hydroxy ) prolineamide nitrogen oxides, o-(carbonitrile)(hydroxy)prolineamide nitrogen oxides, o-(benzaldehyde)(hydroxy)prolineamide nitrogen oxides, o-(olefin)(hydroxy)prolineamide nitrogen oxides, o-(ester)(hydroxy)prolineamide nitrogen oxides, o-(amide)(hydroxy)prolineamide nitrogen oxides, o-(urea)(hydroxy)prolineamide nitrogen oxides, o-(thiourea)(hydroxy)prolineamide nitrogen oxides, o-(oxazoline)(hydroxy)prolineamide nitrogen oxides, o-(imidazole)(hydroxy)prolineamide nitrogen oxides, o-(benzimidazole)(hydroxy)prolineamide nitrogen oxides, o-(thiazole)(hydroxy)prolineamide nitrogen oxides, o-(benzo Thiazoles (hydroxy) proline amide nitrogen oxides, o-(triazoles) (hydroxy) proline amide nitrogen oxides, o-(tetrazolyls) (hydroxy) proline amide nitrogen oxides, o-(p-methylbenzenesulfonamide) (hydroxy) proline oxazoline nitrogen oxides, o-(methylsulfonamide) (hydroxy) proline oxazoline nitrogen oxides, o-(p-nitrobenzenesulfonamide) (hydroxy) proline oxazoline nitrogen oxides, o-(carbonitrile) (hydroxy) proline oxazoline nitrogen oxides, o-(benzaldehyde) (hydroxy) proline oxazoline nitrogen oxides, o-(olefins) (hydroxy) proline oxazoline nitrogen oxides, o-(esters) (hydroxy) proline oxazoline nitrogen oxides, o-(amides) (hydroxy) proline oxazoline nitrogen oxides,o-(urea) (hydroxy) prolyl oxazoline nitrogen oxides, o-(thiourea) (hydroxy) prolyl oxazoline nitrogen oxides, o-(oxazoline) (hydroxy) prolyl oxazoline nitrogen oxides, o-(imidazole) (hydroxy) prolyl oxazoline nitrogen oxides, o-(benzimidazole) (hydroxy) prolyl oxazoline nitrogen oxides, o-(thiazole) (hydroxy) prolyl oxazoline nitrogen oxides, o-(benzothiazole) (hydroxy) prolyl oxazoline nitrogen oxides, o-(triazole) (hydroxy) prolyl oxazoline nitrogen oxides, o-(tetrazolyl) (hydroxy) prolyl oxazoline nitrogen oxides, etc., such as, Figures 4a-4d Indicates.

[0077] Figures 4a-4d In the formula, R c , R d , R f , R 1 , R 2 , R 4 , R 5 , R 6 , R 7a , R 8a , R 11 , R 12 , R 13 , R 14 , R 21 , R 22 , R 23 , R 24 , R 25 , R 28a , R 29a , R 33 , R 34 , R 35 , R 36 , R 37 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48Each is independently selected from a hydrogen atom, a C1-C30 alkyl group, a C1-C30 silyl group, a C1-C30 haloalkyl group, a C2-C30 alkenyl group, a C2-C30 alkynyl group, a halogen (F, Cl, Br, I), a hydroxyl group, an alkoxy group, an acyloxy group, a mercapto group, a thioether group, a nitro group, a carbonyl group, a carboxyl group, an ester group, an amino group and a substituted amino group, an imino group, a cyano group, an amide group, a phosphoamido group, a sulfonamide group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group, and an electron-withdrawing or electron-donating protecting group or an arbitrary substituent group having a chain length of C1-C30; it can also be selected from a substituted or unsubstituted C6-C50 aromatic The invention can be any of a substituted or unsubstituted C7-C50 aralkyl group, a substituted or unsubstituted C7-C50 aralkyloxy group, a substituted or unsubstituted C7-C50 aralkylthiol group, a substituted or unsubstituted C7-C50 aromatic heterocyclic group, a substituted or unsubstituted C7-C30 aromatic amine group, any aromatic heterocyclic group (such as thienyl, benzothienyl, fluorenyl, furanyl, benzofuranyl, benzopyrrolyl, pyridyl, quinolyl, benzoquinolyl, etc.), a substituted heterocyclic group, a fused heterocyclic group (such as tetrahydroquinolyl, dihydroindole, dihydropyranyl, etc.), etc.

[0078] Furthermore, Figures 5a-5f The representative structural compounds shown have the potential to serve as small molecule chiral catalysts and chiral ligands, and can catalyze different types of asymmetric reactions alone or after coordination with metals. Figures 5a-5f In the compounds shown: R 2u , R 2c , R 3c , R 5 , R 6 , R 7a , R 8a , R 14 , R 36 , R 37 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50Each is independently selected from a hydrogen atom, a C1-C30 alkyl group, a C1-C30 silyl group, a C1-C30 haloalkyl group, a C2-C30 alkenyl group, a C2-C30 alkynyl group, a halogen (F, Cl, Br, I), a hydroxyl group, an alkoxy group, an acyloxy group, a mercapto group, a thioether group, a nitro group, a carbonyl group, a carboxyl group, an ester group, an amino group and a substituted amino group, an imino group, a cyano group, an amide group, a phosphoamido group, a sulfonamide group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group, and an electron-withdrawing or electron-donating protecting group or an arbitrary substituent group having a chain length of C1-C30; it can also be selected from a substituted or unsubstituted C6-C50 aromatic The invention can be any of a substituted or unsubstituted C7-C50 aralkyl group, a substituted or unsubstituted C7-C50 aralkyloxy group, a substituted or unsubstituted C7-C50 aralkylthiol group, a substituted or unsubstituted C7-C50 aromatic heterocyclic group, a substituted or unsubstituted C7-C30 aromatic amine group, any aromatic heterocyclic group (such as thienyl, benzothienyl, fluorenyl, furanyl, benzofuranyl, benzopyrrolyl, pyridyl, quinolyl, benzoquinolyl, etc.), a substituted heterocyclic group, a fused heterocyclic group (such as tetrahydroquinolyl, dihydroindole, dihydropyranyl, etc.), etc.

[0079] In a detailed embodiment, the present invention uses chiral secondary amines such as chiral (hydroxy) diphenylprolinol as an example, and undergoes nucleophilic substitution reaction and nitro reduction reaction with o-fluoronitrobenzene to obtain o-aryl chiral diamine compound (II), and o-aryl chiral diamine compound (II) can be prepared by conventional methods (such as direct alkylation or reductive amination, etc.) to obtain amino monosubstituted compound (II-2), and compound (II-2) is acylated, sulfonylated, phosphonylated, etc. according to known or published methods to obtain acylated compound (II-1), and further a suitable oxidant O1 is selected to selectively oxidize the chiral tertiary amine to obtain the target chiral nitrogen oxide (NO) compound. Including but not limited to Figure 8 The synthetic route described herein comprises the following independent, combined or "one-pot" steps:

[0080] (1) Using o-fluoronitrobenzene as the starting material, at temperature T1, solvent S1, and base B1, it undergoes SNAr2 reaction with a chiral prolinol compound C1, and then undergoes nitro reduction to form an o-aryl chiral diamine compound (II);

[0081] Solvent S1 is an inert solvent that can dissolve the substrate but does not react with the substrate, including but not limited to alcohol solvents: such as anhydrous methanol, anhydrous ethanol, tert-butanol, n-butanol, etc.; halogenated hydrocarbon solvents: dichloromethane, chloroform, carbon tetrachloride, etc.; ether solvents: tert-methyl ether, tetrahydrofuran, dioxane (1,6-dioxane), etc., and tert-butanol is usually selected as the reaction solvent.

[0082] Base B1 includes, but is not limited to, one or more of inorganic bases such as sodium carbonate and potassium carbonate and organic bases such as triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), and 4-dimethylaminopyridine (DMAP).

[0083] The ratio of o-fluoronitrobenzene to secondary amine substrate is generally between 1:1.2 and 1:1.5 molar equivalents, usually 1:1.2 is sufficient; the amount of base is between 2.5 and 3 molar equivalents, usually 3 equivalents is sufficient.

[0084] The reaction temperature is the reflux temperature of the solvent, which is usually 25°C to 120°C, and generally 85°C to 100°C. The reaction time is determined by whether the main raw material o-fluoronitrobenzene is completed, and usually more than 18 hours of reaction are required to obtain the intermediate o-nitro chiral aromatic amine compound.

[0085] (2) Nitro reduction reactions can usually be carried out by hydrogen reduction catalyzed by precious metals (palladium, nickel, ruthenium, rhodium, etc.), MLiH4, MBH4, and chemical reduction methods such as metal and (zinc, iron, etc.) acid, including but not limited to Fig. 9 Representative methods are shown.

[0086] The intermediate o-nitro chiral aromatic amine compound is catalytically reduced under the action of a reducing agent R1 such as palladium carbon Pd / C, zinc powder, iron powder, and hydrosulfite, in a suitable solvent S2 and at a suitable temperature T2 to synthesize the target o-aryl chiral diamine compound (II).

[0087] Among them, the reducing agent R1 can be selected from palladium carbon Pd / C, zinc powder, iron powder, insurance powder, metal chloride, etc., the amount of palladium carbon Pd / C is 5% to 10% of the amount of o-fluoronitrobenzene substrate, and the amount of zinc powder, iron powder, etc. is an equivalent amount to the substrate; the reaction solvent S2 is an inert solvent that can dissolve the substrate but does not react with the substrate, including but not limited to: alcohol solvents: such as anhydrous methanol, anhydrous ethanol, etc.; ether solvents: tertiary methyl ether, tetrahydrofuran, dioxane (1,6-dioxane), etc., usually anhydrous methanol or tetrahydrofuran is used as the reaction solvent; the reaction temperature is suitable between 25°C and 60°C, usually at room temperature, if the reaction is slow, the temperature can be gradually increased, usually 60°C to 70°C is more suitable; the reaction time is determined by whether the main raw material o-nitro chiral aromatic amine has reacted completely, and the reaction time is usually 3 hours to 12 hours.

[0088] In addition, the reduction of the intermediate o-nitro chiral aromatic amine compounds requires the addition of different protic solvents S3 according to the different reducing agents. The amount of acid solvent S3 is generally between 2 and 5 times the amount of o-fluoronitrobenzene substrate, and its types include but are not limited to acetic acid, dilute hydrochloric acid, etc. After the reaction is completed, a saturated sodium bicarbonate aqueous solution is added to quench the reaction, and the pH value is adjusted to neutral to weakly alkaline (pH 7-9). The crude o-aryl chiral diamine compound can be obtained by filtration, and the conventional purification methods such as conventional water washing (desalting), crystallization or column can be used to obtain a high-quality target product. However, the pure o-phenylenediamine product is unstable and needs to be further formed into a hydrochloride for room temperature storage.

[0089] (3) A method for preparing a target axial chiral nitrogen oxide (NO) compound by selective nitrogen oxidation of a chiral tertiary amine under the conditions of solvent S4 and temperature T4 is as follows: Fig.10 shown.

[0090] The oxidant O1 includes meta-chloroperbenzoic acid, peracetic acid, peroxysulfuric acid, hydrogen peroxide, ruthenium trichloride, etc., preferably meta-chloroperbenzoic acid as the oxidant, and the amount used is usually between 2.5 and 4 molar equivalents of the amount of the substrate, usually 3 equivalents;

[0091] Solvent S4 is an inert solvent that can dissolve the substrate but does not react with the substrate, including but not limited to one or more of halogenated hydrocarbons, ethers and nitrile solvents, and dichloromethane is usually selected as the solvent;

[0092] The reaction temperature T4 is usually between -78°C and 20°C, and is generally between -10°C and 0°C. The reaction time is determined by whether the main raw materials have reacted completely, and the reaction time is usually between 8 hours and 24 hours.

[0093] The above-mentioned synthetic route provided by the present invention uses low-cost o-fluoronitrobenzene as a starting material, and reacts with a large sterically hindered chiral secondary amine compound at a suitable temperature T1 in a suitable solvent S1 under the action of a base B1 to form an o-nitro chiral aromatic amine intermediate.

[0094] The present invention also provides a series of representative structural compounds, which have the potential to be used as small molecule chiral catalysts and chiral ligands, and can catalyze different types of asymmetric reactions alone or after coordination with metals. Including but not limited to Fig.11 The compounds shown.

[0095] The following specific examples are used to study the effects of the axially chiral aromatic tertiary amine nitrogen oxide ligand compound of the present invention, its preparation method and application. The representative compounds in the examples are as follows: Fig.12 shown.

[0096] Embodiment 1:

[0097] This embodiment provides a method for synthesizing an axially chiral aromatic nitrogen oxide (NO) compound (Ia-1). Fig.13 shown.

[0098] The preparation process is as follows:

[0099] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolinol (1.2 eq.) in a 25 mL round-bottom flask, add appropriate amounts of tert-butyl alcohol and anhydrous potassium carbonate (3 eq.), stir magnetically, and raise the temperature to about 90°C to allow it to fully reflux. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was completely detected by TLC, the reaction was terminated, the reaction was filtered, and the solvent was removed by vacuum rotary evaporation to obtain a crude product, which was separated and purified by column chromatography to obtain an o-nitroaniline intermediate; 3 molar equivalents of glacial acetic acid and zinc powder (slowly added), an appropriate amount of tetrahydrofuran was added, the temperature was lowered to 0°C, and magnetic stirring was performed. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was completely detected by TLC, the reaction was terminated, saturated sodium bicarbonate solution was added to quench, the pH was adjusted to alkaline, tetrahydrofuran was removed by vacuum rotary evaporation, appropriate amounts of water and dichloromethane were added for extraction, the aqueous phase was discarded, anhydrous sodium sulfate was added for washing, the product was filtered, dichloromethane was removed by vacuum rotary evaporation, and the product (II) was separated and purified by column chromatography; then the o-phenylenediamine intermediate was connected to a steric group by a substitution reaction, that is, the o-phenylenediamine intermediate (1 eq.) and methylsulfonic anhydride (1.5 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of dichloromethane was added. as solvent, pyridine (1.5 eq.) was weighed as base, and magnetic stirring was carried out at room temperature overnight. The reaction of the raw material was detected by TLC to be complete, and the reaction was terminated. A dilute hydrochloric acid solution was added and stirred for half an hour, and appropriate amounts of water and dichloromethane were added for extraction. The aqueous phase was discarded, anhydrous sodium sulfate was added for washing, filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The compound obtained by column chromatography was used for the next step of selective nitrogen oxidation reaction; an appropriate amount of dichloromethane was added as solvent to dissolve the raw material, the reaction solution was cooled to 0°C, and an oxidant m-chloroperbenzoic acid (2.5 eq.) was added, and magnetic stirring was carried out for 8 to 10 hours. The reaction of the raw material was detected by TLC to be complete, and the reaction was terminated. A saturated sodium bicarbonate solution was added to quench, and the pH was adjusted to neutral. An appropriate amount of water and dichloromethane were added for extraction, and the aqueous phase was discarded. Anhydrous sodium sulfate was added for washing, filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰa-1) was obtained by column chromatography separation and purification.

[0100] The characterization data of (Ⅰa-1) are as follows: mp: 165~167℃; 1H NMR (400MHz, Chloroform-d) δ14.68(s,1H),9.18(s,1H),7.56–7.49(m,2H),7.36–7.31(m,2H),7.31–7.26(m,3H),7.19–7.05(m,3H),6.95–6.79(m,4H),5.36(dd,J=9.5,7.6Hz,1H),3.96–3.80(m,2H),2.85(s,3H),2.77–2.53(m,2H),2.22(m,1H),2.06(m,1H).13C NMR(101MHz,Chloroform-d)δ145.89,143.83,129.79,128.43,127.53,127.01,126.25,124 .92,121.70(d,J=20.2Hz),120.49,83.31,79.31,78.33,40.09,25.43,22.1.HRMS(ESI)m / z calcd for C24H26N2O4SNa+(M+Na)+461.1505, found 461.1507.

[0101] Example 2

[0102] The product (Ia-1) was obtained in the same yield by replacing the solvent tert-butyl alcohol in the first step of Example 1 with n-butyl alcohol and keeping other conditions the same.

[0103] Example 3

[0104] The solvent of the first step in Example 1 was replaced by chloroform, the temperature was adjusted from 90°C to 50°C, and the other conditions were the same. The product (Ia-1) was obtained in the same yield.

[0105] Embodiment 4:

[0106] The base anhydrous potassium carbonate in the first step of Example 1 was replaced by anhydrous sodium carbonate, and the other conditions were the same to obtain the product (Ia-1) in the same yield.

[0107] Embodiment 5:

[0108] The product (Ia-1) was obtained in the same yield by replacing the base anhydrous potassium carbonate in the first step of Example 1 with anhydrous cesium carbonate and keeping the other conditions the same.

[0109] Embodiment 6:

[0110] The base anhydrous potassium carbonate in the first step of Example 1 was replaced by triethylamine, and the other conditions were the same to obtain the product (Ia-1) in the same yield.

[0111] Embodiment 7:

[0112] The solvent tetrahydrofuran in the second step of Example 1 was replaced with dichloromethane, and other conditions were the same to obtain the product (Ia-1) in a slightly higher yield.

[0113] Embodiment 8:

[0114] The solvent tetrahydrofuran in the second step of Example 1 was replaced with dioxane, and other conditions were the same to obtain the product (Ia-1) in the same yield.

[0115] Embodiment 9:

[0116] The solvent tetrahydrofuran in the second step of Example 1 was replaced with 1,2-dichloroethane, and other conditions were the same to obtain the product (Ia-1) in the same yield.

[0117] Embodiment 10:

[0118] The solvent tetrahydrofuran in the second step of Example 1 was replaced with acetonitrile, and other conditions were the same to obtain the product (Ia-1) in a slightly lower yield.

[0119] Embodiment 11:

[0120] The solvent tetrahydrofuran in the second step of Example 1 was replaced with anhydrous methanol, zinc powder was replaced with Raney nickel, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same. The product (Ia-1) was obtained with a slightly higher yield.

[0121] Embodiment 12:

[0122] The solvent tetrahydrofuran in the second step of Example 1 was replaced with anhydrous methanol, zinc powder was replaced with Pd / C, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same. The product (Ia-1) was obtained with a slightly lower yield.

[0123] Embodiment 13:

[0124] The zinc powder in the second step of Example 1 was replaced by iron powder, the glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water system, and other conditions were the same. The product (Ia-1) was obtained with a slightly lower yield.

[0125] Embodiment 14:

[0126] The zinc powder in the second step of Example 1 was replaced by tin dichloride, the glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water, the temperature was raised to 50°C, and other conditions remained unchanged to obtain the product (Ia-1) with a slightly lower yield.

[0127] Embodiment 15:

[0128] The solvent dichloromethane in the third step of Example 1 was replaced by acetonitrile while keeping other conditions unchanged, and the product (Ia-1) was obtained in a slightly lower yield.

[0129] Embodiment 16:

[0130] The solvent dichloromethane in the third step of Example 1 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged to obtain the product (Ia-1) with the same yield.

[0131] Embodiment 17:

[0132] The solvent dichloromethane in the third step of Example 1 was replaced with tetrahydrofuran, and the other conditions remained unchanged to obtain the product (Ia-1) in the same yield.

[0133] Embodiment 18:

[0134] The solvent dichloromethane in the third step of Example 1 was replaced with ethyl acetate, and the other conditions remained unchanged to obtain the product (Ia-1) with the same yield.

[0135] Embodiment 19:

[0136] The solvent dichloromethane in the third step of Example 1 was replaced by toluene, and the other conditions remained unchanged to obtain the product (Ia-1) in the same yield.

[0137] Embodiment 20:

[0138] The solvent dichloromethane in the third step of Example 1 was replaced with N,N-dimethylformamide, and the other conditions remained unchanged to obtain the product (Ia-1) in the same yield.

[0139] Embodiment 21:

[0140] The base pyridine in the third step of Example 1 was replaced by triethylamine, and the other conditions remained unchanged to obtain the product (Ia-1) in the same yield.

[0141] Embodiment 22:

[0142] The product (Ia-1) was obtained in the same yield by replacing the oxidant m-chloroperbenzoic acid in the fourth step of Example 1 with hydrogen peroxide and the solvent with methanol and water system while keeping other conditions unchanged.

[0143] Embodiment 23:

[0144] The product (Ia-1) was obtained in the same yield by replacing the oxidant m-chloroperbenzoic acid in the fourth step of Example 1 with hydrogen peroxide and the solvent with acetone and water system while keeping other conditions unchanged.

[0145] Embodiment 24:

[0146] The product (Ia-1) was obtained in the same yield by replacing the oxidant m-chloroperbenzoic acid in the fourth step of Example 1 with hydrogen peroxide and the solvent with acetonitrile and water system while keeping other conditions unchanged.

[0147] Embodiment 25:

[0148] The product (Ia-1) was obtained in the same yield by replacing the oxidizing agent m-chloroperbenzoic acid in the fourth step of Example 1 with ruthenium trichloride while keeping other conditions unchanged.

[0149] Embodiment 26:

[0150] The product (Ia-1) was obtained in the same yield by replacing the oxidant m-chloroperbenzoic acid in the fourth step of Example 1 with ruthenium trichloride and the solvent with 1,2-dichloroethane while keeping other conditions unchanged.

[0151] Embodiment 27:

[0152] The solvent dichloromethane in the fourth step of Example 1 was replaced by chloroform, and the other conditions remained unchanged to obtain the product (Ia-1) with the same yield.

[0153] Embodiment 28:

[0154] The solvent dichloromethane in the fourth step of Example 1 was replaced with 1,2-dichloroethane, and the other conditions remained unchanged to obtain the product (Ia-1) with the same yield.

[0155] Embodiment 29:

[0156] The solvent dichloromethane in the fourth step of Example 1 was replaced by acetonitrile, and the other conditions remained unchanged to obtain the product (Ia-1) with the same yield.

[0157] Embodiment 30:

[0158] The solvent dichloromethane in the fourth step of Example 1 was replaced with tetrahydrofuran, while other conditions remained unchanged, and the product (Ia-1) was obtained in a slightly lower yield.

[0159] Embodiment 31:

[0160] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolinol (1.2 eq.) in a 25 mL round-bottom flask, add appropriate amounts of tert-butyl alcohol and anhydrous potassium carbonate (3 eq.), stir magnetically, and raise the temperature to about 90°C to allow it to fully reflux. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was completely detected by TLC, the reaction was terminated, the reaction was filtered, and the solvent was removed by vacuum rotary evaporation to obtain a crude product, which was separated and purified by column chromatography to obtain an o-nitroaniline intermediate; 3 molar equivalents of glacial acetic acid and zinc powder (slowly added), an appropriate amount of tetrahydrofuran was added, the temperature was lowered to 0°C, and magnetic stirring was performed. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was completely detected by TLC, the reaction was terminated, saturated sodium bicarbonate solution was added to quench, the pH was adjusted to alkaline, tetrahydrofuran was removed by vacuum rotary evaporation, appropriate amounts of water and dichloromethane were added for extraction, the aqueous phase was discarded, anhydrous sodium sulfate was added for washing, the product was filtered, dichloromethane was removed by vacuum rotary evaporation, and the product (II) was separated and purified by column chromatography; then the o-phenylenediamine intermediate was connected to a steric group by a substitution reaction, that is, the o-phenylenediamine intermediate (1 eq.) and p-toluenesulfonyl chloride (1.5 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of dichloromethane was added. The reaction mixture was stirred overnight under magnetic stirring at room temperature until the reaction was complete as determined by TLC, and the reaction mixture was terminated. A dilute hydrochloric acid solution was added and stirred for half an hour, and appropriate amounts of water and dichloromethane were added for extraction. The aqueous phase was discarded, anhydrous sodium sulfate was added for washing, the mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The compound obtained by column chromatography was used for the next step of selective nitrogen oxidation reaction. An appropriate amount of dichloromethane was added as a solvent to dissolve the raw materials, the reaction solution was cooled to 0°C, and an oxidant m-chloroperbenzoic acid (2.5 eq.) was added, and magnetic stirring was performed for 8 to 10 hours. The reaction was completed as determined by TLC, and the reaction was terminated. A saturated sodium bicarbonate solution was added for quenching, the pH was adjusted to neutral, appropriate amounts of water and dichloromethane were added for extraction, the aqueous phase was discarded, anhydrous sodium sulfate was added for washing, the mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰa-2) was obtained by column chromatography.

[0161] The characterization data of (Ⅰa-2) are as follows: mp: 157~160℃; 1H NMR (600MHz, Chloroform-d) δ14.75(s,1H),9.32(s,1H),δ7.73–7.68(m,2H),7.52–7.46(m,2H),7.30–7.26(m,3H),7.25–7.21(m,4H),7.20–7.15(m,1H),6.95(ddd,J=8.4,7.2,1.3Hz,1H),6.86(dd,J =8.6,1.3Hz,1H),6.77–6.69(m,4H),5.20(t,J=8.9Hz,1H),3.55(td,J=11.4,7.2Hz,1H),3.32(dd,J =11.1,7.3Hz,1H),2.69(m,1H),2.56–2.42(m,1H),2.37(s,3H),2.21(m,1H),2.00–1.91(m,1H).13C NMR(151MHz,Chloroform-d)δ145.87,143.27,143.16,137.73,135.35,134.96,129.32,129.15,128.31,127.47,127. 28,126.96,126.36,126.24,125.02,122.07,120.85,82.42,78.41,78.07,72.74,25.02,21.61,21.51.HRMS(ESI)m / z calcd for C30H31N2O4S+(M+H)+515.1999,found515.2002.

[0162] Embodiment 32:

[0163] The solvent of the first step in Example 31 was replaced by n-butanol with tert-butanol, and other conditions were the same to obtain the product (Ia-2) in the same yield.

[0164] Embodiment 33:

[0165] The solvent of the first step in Example 31 was replaced by chloroform, the temperature was adjusted from 90°C to 50°C, and the other conditions were the same. The product (Ia-2) was obtained in the same yield.

[0166] Embodiment 34:

[0167] The product (Ia-2) was obtained in the same yield by replacing the base anhydrous potassium carbonate in the first step of Example 31 with anhydrous sodium carbonate and keeping the other conditions the same.

[0168] Embodiment 35:

[0169] The base anhydrous potassium carbonate in the first step of Example 31 was replaced with anhydrous cesium carbonate, and other conditions were the same to obtain the product (Ia-2) in the same yield.

[0170] Embodiment 36:

[0171] The base anhydrous potassium carbonate in the first step of Example 31 was replaced by triethylamine, and the other conditions were the same to obtain the product (Ia-2) in the same yield.

[0172] Embodiment 37:

[0173] The solvent tetrahydrofuran in the second step of Example 31 was replaced with dichloromethane, and other conditions were the same to obtain the product (Ia-2) in a slightly higher yield.

[0174] Embodiment 38:

[0175] The solvent tetrahydrofuran in the second step of Example 31 was replaced with dioxane, and other conditions were the same to obtain the product (Ia-2) in the same yield.

[0176] Embodiment 39:

[0177] The solvent tetrahydrofuran in the second step of Example 31 was replaced with 1,2-dichloroethane, and other conditions were the same to obtain the product (Ia-2) in the same yield.

[0178] Embodiment 40:

[0179] The solvent tetrahydrofuran in the second step of Example 31 was replaced with acetonitrile, and other conditions were the same to obtain the product (Ia-2) in a slightly lower yield.

[0180] Embodiment 41:

[0181] The solvent tetrahydrofuran in the second step of Example 31 was replaced with anhydrous methanol, zinc powder was replaced with Raney nickel, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same to obtain the product (Ia-2) in a slightly higher yield.

[0182] Embodiment 42:

[0183] The solvent tetrahydrofuran in the second step of Example 31 was replaced with anhydrous methanol, zinc powder was replaced with Pd / C, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same. The product (Ia-2) was obtained in a slightly lower yield.

[0184] Embodiment 43:

[0185] The zinc powder in the second step of Example 31 was replaced by iron powder, glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water system, and other conditions were the same to obtain the product (Ia-2) with a slightly lower yield.

[0186] Embodiment 44:

[0187] The zinc powder in the second step of Example 31 was replaced by tin dichloride, the glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water, the temperature was raised to 50°C, and other conditions remained unchanged to obtain the product (Ia-2) in a slightly lower yield.

[0188] Embodiment 45:

[0189] By replacing the dichloromethane solvent in the third step of Example 31 with acetonitrile and keeping other conditions unchanged, the product (Ia-2) was obtained in a slightly lower yield.

[0190] Embodiment 46:

[0191] The solvent dichloromethane in the third step of Example 31 was replaced with 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ia-2) in the same yield.

[0192] Embodiment 47:

[0193] The solvent dichloromethane in the third step of Example 31 was replaced with tetrahydrofuran, and the other conditions remained unchanged to obtain the product (Ia-2) in the same yield.

[0194] Embodiment 48:

[0195] The solvent dichloromethane in the third step of Example 31 was replaced with ethyl acetate, and the other conditions remained unchanged to obtain the product (Ia-2) in the same yield.

[0196] Embodiment 49:

[0197] The solvent dichloromethane in the third step of Example 31 was replaced by toluene, and the other conditions remained unchanged to obtain the product (Ia-2) in the same yield.

[0198] Embodiment 50:

[0199] The solvent dichloromethane in the third step of Example 31 was replaced with N,N-dimethylformamide while keeping other conditions unchanged to obtain the product (Ia-2) in the same yield.

[0200] Embodiment 51:

[0201] The base pyridine in the third step of Example 31 was replaced by triethylamine, and the other conditions remained unchanged to obtain the product (Ia-2) in the same yield.

[0202] Embodiment 52:

[0203] The oxidant m-chloroperbenzoic acid in the fourth step of Example 31 was replaced by hydrogen peroxide, and the solvent was replaced by a methanol and water system. Other conditions remained unchanged, and the product (Ia-2) was obtained in the same yield.

[0204] Embodiment 53:

[0205] The oxidant m-chloroperbenzoic acid in the fourth step of Example 31 was replaced by hydrogen peroxide, and the solvent was replaced by an acetone and water system. Other conditions remained unchanged, and the product (Ia-2) was obtained in the same yield.

[0206] Embodiment 54:

[0207] The oxidant m-chloroperbenzoic acid in the fourth step of Example 31 was replaced by hydrogen peroxide, and the solvent was replaced by acetonitrile and water system. Other conditions remained unchanged, and the product (Ia-2) was obtained in the same yield.

[0208] Embodiment 55:

[0209] The product (Ia-2) was obtained in the same yield by replacing the oxidizing agent m-chloroperbenzoic acid in the fourth step of Example 31 with ruthenium trichloride while keeping other conditions unchanged.

[0210] Embodiment 56:

[0211] The product (Ia-2) was obtained in the same yield by replacing the oxidant m-chloroperbenzoic acid in the fourth step of Example 31 with ruthenium trichloride and the solvent with 1,2-dichloroethane while keeping other conditions unchanged.

[0212] Embodiment 57:

[0213] The solvent dichloromethane in the fourth step of Example 31 was replaced by chloroform while keeping other conditions unchanged to obtain the product (Ia-2) in the same yield.

[0214] Embodiment 58:

[0215] The solvent dichloromethane in the fourth step of Example 31 was replaced with 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ia-2) in the same yield.

[0216] Embodiment 59:

[0217] The solvent dichloromethane in the fourth step of Example 31 was replaced by acetonitrile while keeping other conditions unchanged to obtain the product (Ia-2) in the same yield.

[0218] Embodiment 60:

[0219] By replacing the dichloromethane solvent in the fourth step of Example 31 with tetrahydrofuran and keeping other conditions unchanged, the product (Ia-2) was obtained in a slightly lower yield.

[0220] Example 61:

[0221] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolinol (1.2 eq.) in a 25 mL round-bottom flask, add appropriate amounts of tert-butyl alcohol and anhydrous potassium carbonate (3 eq.), stir magnetically, and raise the temperature to about 90°C to allow it to fully reflux. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was completely detected by TLC, the reaction was terminated, the mixture was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, which was separated and purified by column chromatography to obtain an o-nitroaniline intermediate; 3 molar equivalents of glacial acetic acid and zinc powder (slowly added), an appropriate amount of tetrahydrofuran was added, the temperature was lowered to 0°C, and magnetic stirring was performed. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was completely detected by TLC, the reaction was terminated, saturated sodium bicarbonate solution was added for quenching, the pH was adjusted to alkaline, tetrahydrofuran was removed by rotary evaporation under reduced pressure, appropriate amounts of water and dichloromethane were added for extraction, the aqueous phase was discarded, anhydrous sodium sulfate was added for washing, the mixture was filtered, dichloromethane was removed by rotary evaporation under reduced pressure, and the product (II) was separated and purified by column chromatography; subsequently, the o-phenylenediamine intermediate was connected to a steric group by a substitution reaction, that is, the o-phenylenediamine intermediate (1 eq.) and 4-nitrobenzenesulfonyl chloride (1.5 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of dichloromethane was added. The reaction mixture was stirred overnight under magnetic stirring at room temperature until the reaction was complete as determined by TLC, and the reaction mixture was terminated. A dilute hydrochloric acid solution was added and stirred for half an hour, and appropriate amounts of water and dichloromethane were added for extraction. The aqueous phase was discarded, anhydrous sodium sulfate was added for washing, the mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The compound obtained by column chromatography was used for the next step of selective nitrogen oxidation reaction. An appropriate amount of dichloromethane was added as a solvent to dissolve the raw materials, the reaction solution was cooled to 0°C, and an oxidant m-chloroperbenzoic acid (2.5 eq.) was added, and magnetic stirring was performed for 8 to 10 hours. The reaction was completed as determined by TLC, and the reaction was terminated. A saturated sodium bicarbonate solution was added for quenching, the pH was adjusted to neutral, appropriate amounts of water and dichloromethane were added for extraction, the aqueous phase was discarded, anhydrous sodium sulfate was added for washing, the mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰa-3) was obtained by column chromatography.

[0222] The characterization data of (Ⅰa-3) are as follows: mp: 158~162℃; 1H NMR (600MHz, Chloroform-d) δ8.29–8.24 (m, 2H), 8.00–7.96 (m, 2H), 7.51–7.46 (m, 2H), 7.28 (t, J=7.8Hz, 2H), 7.26–7.24 (m, 2H), 7.22 (dd, J=8.3,1.5Hz, 1H), 7.20–7.15 (m, 1H), 7.04–6.96 (m, 2H), 6.87 (ddd, J=8.6, 7.2,1.5Hz,1H),6.83–6.79(m,3H),5.25(dd,J=9.5,8.1Hz,1H),4.12(q,J=7.2Hz,1H),3.68(td,J=11.3,7. 0Hz,1H),3.36(dd,J=11.0,7.2Hz,1H),2.70(m,1H),2.60–2.48(m,1H),2.29–2.15(m,1H),2.04(m,1H).13C NMR(151MHz,Chloroform-d)δ149.85,146.50,145.55,143.11,135.04,134.95,129.62,128.42(d,J=2.3Hz),127.58 ,127.08,126.44,126.04,124.84,123.97,122.77,121.82,121.19,83.89,79.31,78.15,25.21,22.00.HRMS(ESI)m / z calcd for C29H27N3O6SNa+(M+Na)+568.1513, found 568.1516.

[0223] Embodiment 62:

[0224] The product (Ia-3) was obtained in the same yield by replacing the solvent tert-butyl alcohol in the first step of Example 61 with n-butyl alcohol and keeping other conditions the same.

[0225] Embodiment 63:

[0226] The solvent of the first step in Example 61 was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and the other conditions were the same. The product (Ia-3) was obtained in the same yield.

[0227] Embodiment 64:

[0228] The product (Ia-3) was obtained in the same yield by replacing the base anhydrous potassium carbonate in the first step of Example 61 with anhydrous sodium carbonate and keeping the other conditions the same.

[0229] Embodiment 65:

[0230] The base anhydrous potassium carbonate in the first step of Example 61 was replaced with anhydrous cesium carbonate, and other conditions were the same to obtain the product (Ia-3) in the same yield.

[0231] Embodiment 66:

[0232] The base anhydrous potassium carbonate in the first step of Example 61 was replaced by triethylamine, and the other conditions were the same to obtain the product (Ia-3) in the same yield.

[0233] Embodiment 67:

[0234] The solvent tetrahydrofuran in the second step of Example 61 was replaced with dichloromethane, and other conditions were the same to obtain the product (Ia-3) in a slightly higher yield.

[0235] Embodiment 68:

[0236] The solvent tetrahydrofuran in the second step of Example 61 was replaced with dioxane, and other conditions were the same to obtain the product (Ia-3) in the same yield.

[0237] Embodiment 69:

[0238] The solvent tetrahydrofuran in the second step of Example 61 was replaced with 1,2-dichloroethane, and other conditions were the same to obtain the product (Ia-3) in the same yield.

[0239] Embodiment 70:

[0240] The solvent tetrahydrofuran in the second step of Example 61 was replaced with acetonitrile, and other conditions were the same to obtain the product (Ia-3) in a slightly lower yield.

[0241] Embodiment 71:

[0242] The solvent tetrahydrofuran in the second step of Example 61 was replaced with anhydrous methanol, zinc powder was replaced with Raney nickel, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same to obtain the product (Ia-3) in a slightly higher yield.

[0243] Embodiment 72:

[0244] The solvent tetrahydrofuran in the second step of Example 61 was replaced with anhydrous methanol, zinc powder was replaced with Pd / C, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same. The product (Ia-3) was obtained in a slightly lower yield.

[0245] Embodiment 73:

[0246] The zinc powder in the second step of Example 61 was replaced by iron powder, glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water system, and other conditions were the same to obtain the product (Ia-3) with a slightly lower yield.

[0247] Embodiment 74:

[0248] The zinc powder in the second step of Example 61 was replaced by tin dichloride, the glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water, the temperature was raised to 50°C, and other conditions remained unchanged to obtain the product (Ia-3) in a slightly lower yield.

[0249] Embodiment 75:

[0250] By replacing the dichloromethane solvent in the third step of Example 61 with acetonitrile and keeping other conditions unchanged, the product (Ia-3) was obtained in a slightly lower yield.

[0251] Embodiment 76:

[0252] The solvent dichloromethane in the third step of Example 61 was replaced with 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ia-3) in the same yield.

[0253] Embodiment 77:

[0254] The solvent dichloromethane in the third step of Example 61 was replaced by tetrahydrofuran, and the other conditions remained unchanged to obtain the product (Ia-3) in the same yield.

[0255] Embodiment 78:

[0256] The solvent dichloromethane in the third step of Example 61 was replaced with ethyl acetate, and the other conditions remained unchanged to obtain the product (Ia-3) in the same yield.

[0257] Embodiment 79:

[0258] The solvent dichloromethane in the third step of Example 61 was replaced by toluene, and the other conditions remained unchanged to obtain the product (Ia-3) in the same yield.

[0259] Embodiment 80:

[0260] The solvent dichloromethane in the third step of Example 61 was replaced with N,N-dimethylformamide while keeping other conditions unchanged to obtain the product (Ia-3) in the same yield.

[0261] Embodiment 81:

[0262] The base pyridine in the third step of Example 61 was replaced by triethylamine, and the other conditions remained unchanged to obtain the product (Ia-3) in the same yield.

[0263] Embodiment 82:

[0264] The oxidant m-chloroperbenzoic acid in the fourth step of Example 61 was replaced by hydrogen peroxide, and the solvent was replaced by a methanol and water system. Other conditions remained unchanged, and the product (Ia-3) was obtained in the same yield.

[0265] Embodiment 83:

[0266] The oxidant m-chloroperbenzoic acid in the fourth step of Example 61 was replaced by hydrogen peroxide, and the solvent was replaced by an acetone and water system. Other conditions remained unchanged, and the product (Ia-3) was obtained in the same yield.

[0267] Embodiment 84:

[0268] The oxidant m-chloroperbenzoic acid in the fourth step of Example 61 was replaced by hydrogen peroxide, and the solvent was replaced by acetonitrile and water system. Other conditions remained unchanged, and the product (Ia-3) was obtained in the same yield.

[0269] Embodiment 85:

[0270] By replacing the oxidizing agent m-chloroperbenzoic acid in the fourth step of Example 61 with ruthenium trichloride and keeping other conditions unchanged, the product (Ia-3) was obtained in the same yield.

[0271] Embodiment 86:

[0272] The oxidant m-chloroperbenzoic acid in the fourth step of Example 61 was replaced by ruthenium trichloride, and the solvent was replaced by 1,2-dichloroethane. The other conditions remained unchanged, and the product (Ia-3) was obtained in the same yield.

[0273] Embodiment 87:

[0274] The solvent dichloromethane in the fourth step of Example 61 was replaced by chloroform while keeping other conditions unchanged to obtain the product (Ia-3) in the same yield.

[0275] Embodiment 88:

[0276] The solvent dichloromethane in the fourth step of Example 61 was replaced with 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ia-3) in the same yield.

[0277] Embodiment 89:

[0278] The solvent dichloromethane in the fourth step of Example 61 was replaced by acetonitrile while keeping other conditions unchanged to obtain the product (Ia-3) in the same yield.

[0279] Embodiment 90:

[0280] By replacing the dichloromethane solvent in the fourth step of Example 61 with tetrahydrofuran and keeping other conditions unchanged, the product (Ia-3) was obtained in a slightly lower yield.

[0281] Embodiment 91:

[0282] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolinol (1.2 eq.) in a 25 mL round-bottom flask, add appropriate amounts of tert-butyl alcohol and anhydrous potassium carbonate (3 eq.), stir magnetically, and raise the temperature to about 90°C to allow it to fully reflux. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was completely detected by TLC, the reaction was terminated, filtered, and the solvent was removed by vacuum rotary evaporation to obtain a crude product, which was separated and purified by column chromatography to obtain an o-nitroaniline intermediate; 3 molar equivalents of glacial acetic acid and zinc powder (slowly added), an appropriate amount of tetrahydrofuran was added, the temperature was lowered to 0°C, and magnetic stirring was performed. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was completely detected by TLC, the reaction was terminated, saturated sodium bicarbonate solution was added to quench, the pH was adjusted to alkaline, tetrahydrofuran was removed by vacuum rotary evaporation, appropriate amounts of water and dichloromethane were added for extraction, the aqueous phase was discarded, anhydrous sodium sulfate was added for washing, filtered, dichloromethane was removed by vacuum rotary evaporation, and product (II) was separated and purified by column chromatography; subsequently, the o-phenylenediamine intermediate was further reacted to attach a steric group, that is, the o-phenylenediamine intermediate (1 eq.) and triethylamine (1.5 eq.) were placed in a 25 mL round-bottom flask, an appropriate amount of dichloromethane was added as a solvent, and the reaction solution was cooled to 0 ℃, slowly dropwise add a diluted dichloromethane solution of oxalyl chloride (0.5 eq.), magnetically stir for 2 h at room temperature, detect by TLC that the raw material reacts completely, terminate the reaction, add saturated aqueous ammonium chloride solution and stir for half an hour, add appropriate amount of water and dichloromethane for extraction, discard the aqueous phase, add anhydrous sodium sulfate for washing, filter, and remove dichloromethane by rotary evaporation under reduced pressure. The compound obtained by column chromatography separation and purification is used for the next step of selective nitrogen oxidation reaction; add appropriate amount of dichloromethane as solvent to dissolve the raw material, cool the reaction solution to 0℃, add oxidant m-chloroperbenzoic acid (2.5 eq.), magnetically stir for 8-10 h, detect by TLC that the raw material reacts completely, terminate the reaction, add saturated sodium bicarbonate solution to quench, adjust the pH to neutral, add appropriate amount of water and dichloromethane for extraction, discard the aqueous phase, add anhydrous sodium sulfate for washing, filter, and remove dichloromethane by rotary evaporation under reduced pressure. Separate and purify by column chromatography to obtain the target chiral nitrogen oxide (NO) compound (Ⅰa-4).

[0283] The characterization data of (Ⅰa-4) are as follows: mp: 141~152℃; 1H NMR (400MHz, Chloroform-d) δ15.06(s,1H),8.40(d,J=8.5Hz,1H),7.63–7.59(m,1H),7.58–7.54(m,3H),7.37–7.30(m,12H),7.22–7.07(m,5H),7.03–6.94(m,3H),6.90–6.77(m,4H),5.36–5.26(m,2H),4.09–3.98(m,4H),3.75(m,2H),3.53(m,3H),2.84–2.68(m,3H),2.42–2.02(m,2H).13C NMR (151MHz, Chloroform-d) δ128.32, 127.96, 127.62, 127.06, 126.79 (d, J = 6.8Hz), 126.21, 124. 85,121.08,117.26,84.67,78.08,30.82,29.71,29.34,25.54,22.71,22.27.HRMS(ESI)m / zcalcd for C48H46N4O6Na+(M+Na)+797.3309,found797.3309.

[0284] Embodiment 92:

[0285] The solvent of the first step in Example 91 was replaced by n-butanol with tert-butanol, and other conditions were the same to obtain the product (Ia-4) in the same yield.

[0286] Embodiment 93:

[0287] The solvent of the first step in Example 91 was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and the other conditions were the same. The product (Ia-4) was obtained in the same yield.

[0288] Embodiment 94:

[0289] The product (Ia-4) was obtained in the same yield by replacing the base anhydrous potassium carbonate in the first step of Example 91 with anhydrous sodium carbonate and keeping the other conditions the same.

[0290] Embodiment 95:

[0291] The base anhydrous potassium carbonate in the first step of Example 91 was replaced with anhydrous cesium carbonate, and other conditions were the same to obtain the product (Ia-4) in the same yield.

[0292] Embodiment 96:

[0293] The base anhydrous potassium carbonate in the first step of Example 91 was replaced with triethylamine, and the other conditions were the same to obtain the product (Ia-4) in the same yield.

[0294] Embodiment 97:

[0295] The solvent tetrahydrofuran in the second step of Example 91 was replaced with dichloromethane, and other conditions were the same to obtain the product (Ia-4) in a slightly higher yield.

[0296] Embodiment 98:

[0297] The solvent tetrahydrofuran in the second step of Example 91 was replaced with dioxane, and other conditions were the same to obtain the product (Ia-4) in the same yield.

[0298] Embodiment 99:

[0299] The solvent tetrahydrofuran in the second step of Example 91 was replaced with 1,2-dichloroethane, and other conditions were the same to obtain the product (Ia-4) in the same yield.

[0300] Embodiment 100:

[0301] The solvent tetrahydrofuran in the second step of Example 91 was replaced with acetonitrile, and other conditions were the same to obtain the product (Ia-4) in a slightly lower yield.

[0302] Embodiment 101:

[0303] The solvent tetrahydrofuran in the second step of Example 91 was replaced with anhydrous methanol, zinc powder was replaced with Raney nickel, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same to obtain the product (Ia-4) in a slightly higher yield.

[0304] Embodiment 102:

[0305] The solvent tetrahydrofuran in the second step of Example 91 was replaced with anhydrous methanol, zinc powder was replaced with Pd / C, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same. The product (Ia-4) was obtained in a slightly lower yield.

[0306] Embodiment 103:

[0307] The zinc powder in the second step of Example 91 was replaced by iron powder, glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water system, and other conditions were the same to obtain the product (Ia-4) with a slightly lower yield.

[0308] Embodiment 104:

[0309] The zinc powder in the second step of Example 91 was replaced by tin dichloride, the glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water, the temperature was raised to 50°C, and other conditions remained unchanged to obtain the product (Ia-4) in a slightly lower yield.

[0310] Embodiment 105:

[0311] By replacing the dichloromethane solvent in the third step of Example 91 with acetonitrile and keeping other conditions unchanged, the product (Ia-4) was obtained in a slightly lower yield.

[0312] Embodiment 106:

[0313] The solvent dichloromethane in the third step of Example 91 was replaced with 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ia-4) in the same yield.

[0314] Embodiment 107:

[0315] The solvent dichloromethane in the third step of Example 91 was replaced with tetrahydrofuran, and the other conditions remained unchanged to obtain the product (Ia-4) in the same yield.

[0316] Embodiment 108:

[0317] The solvent dichloromethane in the third step of Example 91 was replaced with 1,2-dioxane while keeping other conditions unchanged to obtain the product (Ia-4) in the same yield.

[0318] Embodiment 109:

[0319] The solvent dichloromethane in the third step of Example 91 was replaced by chloroform while keeping other conditions unchanged to obtain the product (Ia-4) in the same yield.

[0320] Embodiment 110:

[0321] The oxidant m-chloroperbenzoic acid in the fourth step of Example 91 was replaced by hydrogen peroxide, and the solvent was replaced by a methanol and water system. Other conditions remained unchanged, and the product (Ia-4) was obtained in the same yield.

[0322] Embodiment 111:

[0323] The oxidant m-chloroperbenzoic acid in the fourth step of Example 91 was replaced by hydrogen peroxide, and the solvent was replaced by an acetone and water system. Other conditions remained unchanged, and the product (Ia-4) was obtained in the same yield.

[0324] Embodiment 112:

[0325] The oxidant m-chloroperbenzoic acid in the fourth step of Example 91 was replaced by hydrogen peroxide, and the solvent was replaced by acetonitrile and water system. Other conditions remained unchanged, and the product (Ia-4) was obtained in the same yield.

[0326] Embodiment 113:

[0327] By replacing the oxidizing agent m-chloroperbenzoic acid in the fourth step of Example 91 with ruthenium trichloride and keeping other conditions unchanged, the product (Ia-4) was obtained in the same yield.

[0328] Embodiment 114:

[0329] The product (Ia-4) was obtained in the same yield by replacing the oxidant m-chloroperbenzoic acid in the fourth step of Example 91 with ruthenium trichloride and the solvent with 1,2-dichloroethane while keeping other conditions unchanged.

[0330] Embodiment 115:

[0331] The solvent dichloromethane in the fourth step of Example 91 was replaced by chloroform while keeping other conditions unchanged to obtain the product (Ia-4) in the same yield.

[0332] Embodiment 116:

[0333] The solvent dichloromethane in the fourth step of Example 91 was replaced with 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ia-4) in the same yield.

[0334] Embodiment 117:

[0335] The solvent dichloromethane in the fourth step of Example 91 was replaced by acetonitrile while keeping other conditions unchanged to obtain the product (Ia-4) in the same yield.

[0336] Embodiment 118:

[0337] By replacing the dichloromethane solvent in the fourth step of Example 91 with tetrahydrofuran and keeping other conditions unchanged, the product (Ia-4) was obtained in a slightly lower yield.

[0338] Embodiment 119:

[0339] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolinol (1.2 eq.) in a 25 mL round-bottom flask, add appropriate amounts of tert-butyl alcohol and anhydrous potassium carbonate (3 eq.), stir magnetically, and raise the temperature to about 90°C to allow it to fully reflux. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was completely detected by TLC, the reaction was terminated, the reaction was filtered, and the solvent was removed by vacuum rotary evaporation to obtain a crude product, which was separated and purified by column chromatography to obtain an o-nitroaniline intermediate; 3 molar equivalents of glacial acetic acid and zinc powder (slowly added), an appropriate amount of tetrahydrofuran was added, the temperature was lowered to 0°C, and magnetic stirring was performed. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was completely detected by TLC, the reaction was terminated, saturated sodium bicarbonate solution was added to quench, the pH was adjusted to alkaline, tetrahydrofuran was removed by vacuum rotary evaporation, appropriate amounts of water and dichloromethane were added for extraction, the aqueous phase was discarded, anhydrous sodium sulfate was added for washing, the product was filtered, dichloromethane was removed by vacuum rotary evaporation, and the product (II) was separated and purified by column chromatography; then the o-phenylenediamine intermediate was connected to a steric group through a condensation reaction, that is, the o-phenylenediamine intermediate (1 eq.) and 2-cyanobenzenesulfonyl chloride (1.2 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of dichloro Methane is used as solvent, pyridine (1.5 eq.) is weighed as base, and magnetic stirring is carried out at room temperature overnight. The reaction of the raw material is detected by TLC to be completely reacted, and the reaction is terminated. A dilute hydrochloric acid aqueous solution is added and stirred for half an hour, and appropriate amounts of water and dichloromethane are added for extraction. The aqueous phase is discarded, anhydrous sodium sulfate is added for washing, filtered, and dichloromethane is removed by rotary evaporation under reduced pressure. The compound obtained by column chromatography separation and purification is used for the next step of selective nitrogen oxidation reaction; an appropriate amount of dichloromethane is added as solvent to dissolve the raw material, the reaction solution is cooled to 0°C, and an oxidant m-chloroperbenzoic acid (2.5 eq.) is added, and magnetic stirring is carried out for 8 to 10 hours. The reaction of the raw material is detected by TLC to be completely reacted, and the reaction is terminated. A saturated sodium bicarbonate solution is added for quenching, the pH is adjusted to neutral, and appropriate amounts of water and dichloromethane are added for extraction. The aqueous phase is discarded, anhydrous sodium sulfate is added for washing, filtered, and dichloromethane is removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰa-5) is separated and purified by column chromatography.

[0340] The characterization data of (Ia-5) are as follows: mp: 133-136°C; 1H NMR (400MHz, Chloroform-d) δ8.19 (d, J = 7.9 Hz, 1H), 7.89 (dd, J = 7.6, 1.4 Hz, 1H), 7.79 (td, J = 7.8, 1.4 Hz, 1H), 7.70 (td, J = 7.6, 1.3 Hz, 1H), 7.61-7.54 (m, 2H), 7.38-7.32 (m, 4H), 7.28-7.20 (m, 1H),7.16(dd,J=8.3,1.5Hz,1H),7.08–6.96(m,2H),6.87–6.75(m,4H),5.35(t,J=8.9Hz,1H),3 .90–3.71(m,2H),2.87–2.75(m,1H),2.65(d,J=9.8Hz,1H),2.39–2.24(m,1H),2.10(m,2H).13C NMR(101MHz,Chloroform-d)δ145.73,143.60,143.22,135.23,134.12,132.73,132.29,129.75,129.53,128.37,127.49,127 .04,126.36(d,J=6.0Hz),125.11,121.96,121.20,120.54,115.97,110.90,83.27,78.53,78.12,24.99,21.77.HRMS(ESI)m / z calcd forC30H27N3O4SNa+(M+Na)+548.1615,found 548.1617.

[0341] Embodiment 120:

[0342] The solvent of the first step in Example 119 was replaced by n-butanol with tert-butanol, and other conditions were the same to obtain the product (Ia-5) in the same yield.

[0343] Embodiment 121:

[0344] The solvent of the first step in Example 119 was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and the other conditions were the same. The product (Ia-5) was obtained in the same yield.

[0345] Embodiment 122:

[0346] The product (Ia-5) was obtained in the same yield by replacing the base anhydrous potassium carbonate in the first step of Example 119 with anhydrous sodium carbonate and keeping the other conditions the same.

[0347] Embodiment 123:

[0348] The base anhydrous potassium carbonate in the first step of Example 119 was replaced with anhydrous cesium carbonate, and other conditions were the same to obtain the product (Ia-5) in the same yield.

[0349] Embodiment 124:

[0350] The base anhydrous potassium carbonate in the first step of Example 119 was replaced with triethylamine, and the other conditions were the same to obtain the product (Ia-5) in the same yield.

[0351] Embodiment 125:

[0352] The solvent tetrahydrofuran in the second step of Example 119 was replaced with dichloromethane, and other conditions were the same to obtain the product (Ia-5) in a slightly higher yield.

[0353] Embodiment 126:

[0354] The solvent tetrahydrofuran in the second step of Example 119 was replaced with dioxane, and other conditions were the same to obtain the product (Ia-5) in the same yield.

[0355] Embodiment 127:

[0356] The solvent tetrahydrofuran in the second step of Example 119 was replaced with 1,2-dichloroethane, and other conditions were the same to obtain the product (Ia-5) in the same yield.

[0357] Embodiment 128:

[0358] The solvent tetrahydrofuran in the second step of Example 119 was replaced with acetonitrile, and other conditions were the same to obtain the product (Ia-5) in a slightly lower yield.

[0359] Embodiment 129:

[0360] The solvent tetrahydrofuran in the second step of Example 119 was replaced with anhydrous methanol, zinc powder was replaced with Raney nickel, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same to obtain the product (Ia-5) in a slightly higher yield.

[0361] Embodiment 130:

[0362] The solvent tetrahydrofuran in the second step of Example 119 was replaced with anhydrous methanol, zinc powder was replaced with Pd / C, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same to obtain the product (Ia-5) in a slightly lower yield.

[0363] Embodiment 131:

[0364] The zinc powder in the second step of Example 119 was replaced by iron powder, glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water system, and other conditions were the same to obtain the product (Ia-5) with a slightly lower yield.

[0365] Embodiment 132:

[0366] The zinc powder in the second step of Example 119 was replaced by tin dichloride, the glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water, the temperature was raised to 50°C, and other conditions remained unchanged to obtain the product (Ia-5) in a slightly lower yield.

[0367] Embodiment 133:

[0368] By replacing the dichloromethane solvent in the third step of Example 119 with acetonitrile and keeping other conditions unchanged, the product (Ia-5) was obtained in a slightly lower yield.

[0369] Embodiment 134:

[0370] The solvent dichloromethane in the third step of Example 119 was replaced with 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ia-5) in the same yield.

[0371] Embodiment 135:

[0372] The solvent dichloromethane in the third step of Example 119 was replaced with tetrahydrofuran, and the other conditions remained unchanged to obtain the product (Ia-5) in the same yield.

[0373] Embodiment 136:

[0374] The solvent dichloromethane in the third step of Example 119 was replaced with ethyl acetate while keeping other conditions unchanged to obtain the product (Ia-5) in the same yield.

[0375] Embodiment 137:

[0376] The solvent dichloromethane in the third step of Example 119 was replaced by toluene while keeping other conditions unchanged to obtain the product (Ia-5) in the same yield.

[0377] Embodiment 138:

[0378] The solvent dichloromethane in the third step of Example 119 was replaced with N,N-dimethylformamide while keeping other conditions unchanged to obtain the product (Ia-5) in the same yield.

[0379] Embodiment 139:

[0380] The base pyridine in the third step of Example 119 was replaced by triethylamine, and the other conditions remained unchanged to obtain the product (Ia-5) in the same yield.

[0381] Embodiment 140:

[0382] The oxidant m-chloroperbenzoic acid in the fourth step of Example 119 was replaced by hydrogen peroxide, and the solvent was replaced by a methanol and water system. Other conditions remained unchanged, and the product (Ia-5) was obtained in the same yield.

[0383] Example 141:

[0384] The oxidant m-chloroperbenzoic acid in the fourth step of Example 119 was replaced by hydrogen peroxide, and the solvent was replaced by an acetone and water system. Other conditions remained unchanged, and the product (Ia-5) was obtained in the same yield.

[0385] Embodiment 142:

[0386] The oxidant m-chloroperbenzoic acid in the fourth step of Example 119 was replaced by hydrogen peroxide, and the solvent was replaced by acetonitrile and water system. Other conditions remained unchanged, and the product (Ia-5) was obtained in the same yield.

[0387] Embodiment 143:

[0388] By replacing the oxidizing agent m-chloroperbenzoic acid in the fourth step of Example 119 with ruthenium trichloride and keeping other conditions unchanged, the product (Ia-5) was obtained in the same yield.

[0389] Embodiment 144:

[0390] The oxidant m-chloroperbenzoic acid in the fourth step of Example 119 was replaced by ruthenium trichloride, and the solvent was replaced by 1,2-dichloroethane. The other conditions remained unchanged, and the product (Ia-5) was obtained in the same yield.

[0391] Embodiment 145:

[0392] The solvent dichloromethane in the fourth step of Example 119 was replaced by chloroform while keeping other conditions unchanged to obtain the product (Ia-5) in the same yield.

[0393] Embodiment 146:

[0394] The solvent dichloromethane in the fourth step of Example 119 was replaced with 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ia-5) in the same yield.

[0395] Embodiment 147:

[0396] The solvent dichloromethane in the fourth step of Example 119 was replaced by acetonitrile while keeping other conditions unchanged to obtain the product (Ia-5) in the same yield.

[0397] Embodiment 148:

[0398] By replacing the dichloromethane solvent in the fourth step of Example 119 with tetrahydrofuran and keeping other conditions unchanged, the product (Ia-5) was obtained in a slightly lower yield.

[0399] Embodiment 149:

[0400] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolinol (1.2 eq.) in a 25 mL round-bottom flask, add appropriate amounts of tert-butyl alcohol and anhydrous potassium carbonate (3 eq.), stir magnetically, and raise the temperature to about 90°C to allow it to fully reflux. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was completely detected by TLC, the reaction was terminated, filtered, and the solvent was removed by vacuum rotary evaporation to obtain a crude product, which was separated and purified by column chromatography to obtain an o-nitroaniline intermediate; 3 molar equivalents of glacial acetic acid and zinc powder (slowly added), an appropriate amount of tetrahydrofuran was added, the temperature was lowered to 0°C, and magnetic stirring was performed. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was completely detected by TLC, the reaction was terminated, saturated sodium bicarbonate solution was added to quench, the pH was adjusted to alkaline, tetrahydrofuran was removed by vacuum rotary evaporation, appropriate amounts of water and dichloromethane were added for extraction, the aqueous phase was discarded, anhydrous sodium sulfate was added for washing, filtered, dichloromethane was removed by vacuum rotary evaporation, and product (II) was separated and purified by column chromatography; then the o-phenylenediamine intermediate was connected to a steric group through a condensation reaction, that is, the o-phenylenediamine intermediate (1 eq.) and 3,5-bis(trifluoromethyl)benzoic acid (1.2 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of Dichloromethane was used as solvent, HATU (1.5 eq.) was weighed as condensing agent, and magnetic stirring was carried out at room temperature overnight. The reaction of the raw material was detected by TLC to be completely reacted, and the reaction was terminated. An aqueous solution was added and stirred for half an hour, and appropriate amounts of water and dichloromethane were added for extraction. The aqueous phase was discarded, anhydrous sodium sulfate was added for washing, filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The compound obtained by column chromatography separation and purification was used for the next step of selective nitrogen oxidation reaction; an appropriate amount of dichloromethane was added as solvent to dissolve the raw material, the reaction solution was cooled to 0°C, and an oxidant m-chloroperbenzoic acid (2.5 eq.) was added, and magnetic stirring was carried out for 8 to 10 hours. The reaction of the raw material was detected by TLC to be completely reacted, and the reaction was terminated. A saturated sodium bicarbonate solution was added for quenching, the pH was adjusted to neutral, and appropriate amounts of water and dichloromethane were added for extraction. The aqueous phase was discarded, anhydrous sodium sulfate was added for washing, filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰa-6) was obtained by column chromatography separation and purification.

[0401] The characterization data of (Ⅰa-6) are as follows: mp: 165~171℃; 1H NMR (400MHz, Chloroform-d) δ15.38(s,1H),8.93(s,1H),8.52(dd,J=8.3,1.5Hz,1H),8.23(d,J=1.7Hz,2H),7.95(s,1H),7.48–7.38(m,2H),7.28–7.11(m,6H),7.12–6.93(m,2 H),6.74(t,J=7.3Hz,1H),6.62(t,J=7.6Hz,2H),5.32(dd,J=9.7,6.1Hz,1H),4.00(td, J=10.9,6.3Hz,1H),3.91(m,1H),2.68–2.54(m,2H),2.14(m,1H),2.08–1.91(m,1H).13C NMR(101MHz,Chloroform-d)δ160.11,144.37,142.98,136.73,135.35,134.93,131.35(d,J=33.7Hz),130.68(d,J=33.7Hz),128.63,127.4 3,126.61(d,J=4.1Hz),126.33,125.97,125.46,124.54,123.71,121.83,121.65,120.09,85.36,79.80,77.57,25.20,22.20.HRMS(ESI)m / z calcd forC32H26F6N2O3Na+(M+Na)+623.1740,found623.1740.

[0402] The crystal data of (Ⅰa-6) are shown in Table 1-9.

[0403]

[0404] Table 1 Crystal data and structure refinement of Ⅰa-6

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415] Table 4 Bond lengths of Ⅰa-6

[0416]

[0417]

[0418]

[0419] Table 5 Bond angles of Ⅰa-6

[0420]

[0421]

[0422]

[0423]

[0424]

[0425] Table 7 Torque angle of Ⅰa-6

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433] Embodiment 150:

[0434] The solvent of the first step in Example 149 was replaced by n-butanol with tert-butanol, and the other conditions were the same to obtain the product (Ia-6) in the same yield.

[0435] Embodiment 151:

[0436] The solvent of the first step in Example 149 was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and the other conditions were the same to obtain the product (Ia-6) in the same yield.

[0437] Embodiment 152:

[0438] The base anhydrous potassium carbonate in the first step of Example 149 was replaced with anhydrous sodium carbonate, and other conditions were the same to obtain the product (Ia-6) in the same yield.

[0439] Embodiment 153:

[0440] The base anhydrous potassium carbonate in the first step of Example 149 was replaced with anhydrous cesium carbonate, and other conditions were the same to obtain the product (Ia-6) in the same yield.

[0441] Embodiment 154:

[0442] The base anhydrous potassium carbonate in the first step of Example 149 was replaced by triethylamine, and the other conditions were the same to obtain the product (Ia-6) in the same yield.

[0443] Embodiment 155:

[0444] The solvent tetrahydrofuran in the second step of Example 149 was replaced with dichloromethane, and other conditions were the same to obtain the product (Ia-6) in a slightly higher yield.

[0445] Embodiment 156:

[0446] The solvent tetrahydrofuran in the second step of Example 149 was replaced with dioxane, and other conditions were the same to obtain the product (Ia-6) in the same yield.

[0447] Embodiment 157:

[0448] The solvent tetrahydrofuran in the second step of Example 149 was replaced with 1,2-dichloroethane, and other conditions were the same to obtain the product (Ia-6) in the same yield.

[0449] Embodiment 158:

[0450] The solvent tetrahydrofuran in the second step of Example 149 was replaced with acetonitrile, and other conditions were the same to obtain the product (Ia-6) in a slightly lower yield.

[0451] Embodiment 159:

[0452] The solvent tetrahydrofuran in the second step of Example 149 was replaced with anhydrous methanol, zinc powder was replaced with Raney nickel, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same to obtain the product (Ia-6) in a slightly higher yield.

[0453] Embodiment 160:

[0454] The solvent tetrahydrofuran in the second step of Example 149 was replaced with anhydrous methanol, zinc powder was replaced with Pd / C, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same to obtain the product (Ia-6) in a slightly lower yield.

[0455] Example 161:

[0456] The zinc powder in the second step of Example 149 was replaced by iron powder, glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water system, and other conditions were the same to obtain the product (Ia-6) with a slightly lower yield.

[0457] Embodiment 162:

[0458] The zinc powder in the second step of Example 149 was replaced by tin dichloride, the glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water, the temperature was raised to 50°C, and other conditions remained unchanged to obtain the product (Ia-6) in a slightly lower yield.

[0459] Embodiment 163:

[0460] By replacing the dichloromethane solvent in the third step of Example 149 with acetonitrile and keeping other conditions unchanged, the product (Ia-6) was obtained in a slightly lower yield.

[0461] Embodiment 164:

[0462] The solvent dichloromethane in the third step of Example 149 was replaced with 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ia-6) in the same yield.

[0463] Embodiment 165:

[0464] The solvent dichloromethane in the third step of Example 149 was replaced by tetrahydrofuran, and the other conditions remained unchanged to obtain the product (Ia-6) in the same yield.

[0465] Example 166:

[0466] The solvent dichloromethane in the third step of Example 149 was replaced with 1,2-dioxane while other conditions remained unchanged to obtain the product (Ia-6) in the same yield.

[0467] Example 167:

[0468] The solvent dichloromethane in the third step of Example 149 was replaced by tetrahydrofuran, and the other conditions remained unchanged to obtain the product (Ia-6) in the same yield.

[0469] Embodiment 168:

[0470] The solvent dichloromethane in the third step of Example 149 was replaced with N,N-dimethylformamide while keeping other conditions unchanged to obtain the product (Ia-6) in the same yield.

[0471] Embodiment 169:

[0472] The condensation agent HATU in the third step of Example 149 was replaced by CDI, and nitrogen protection was used. The other conditions remained unchanged to obtain the product (Ia-6) in the same yield.

[0473] Embodiment 170:

[0474] The product (Ia-6) was obtained in the same yield by replacing the oxidant m-chloroperbenzoic acid in the fourth step of Example 149 with hydrogen peroxide and the solvent with methanol and water system while keeping other conditions unchanged.

[0475] Embodiment 171:

[0476] The oxidant m-chloroperbenzoic acid in the fourth step of Example 149 was replaced by hydrogen peroxide, and the solvent was replaced by an acetone and water system. Other conditions remained unchanged, and the product (Ia-6) was obtained in the same yield.

[0477] Embodiment 172:

[0478] The oxidant m-chloroperbenzoic acid in the fourth step of Example 149 was replaced by hydrogen peroxide, and the solvent was replaced by acetonitrile and water system. Other conditions remained unchanged, and the product (Ia-6) was obtained in the same yield.

[0479] Embodiment 173:

[0480] By replacing the oxidizing agent m-chloroperbenzoic acid in the fourth step of Example 149 with ruthenium trichloride and keeping other conditions unchanged, the product (Ia-6) was obtained in the same yield.

[0481] Embodiment 174:

[0482] The oxidant m-chloroperbenzoic acid in the fourth step of Example 149 was replaced by ruthenium trichloride, and the solvent was replaced by 1,2-dichloroethane. The other conditions remained unchanged, and the product (Ia-6) was obtained in the same yield.

[0483] Embodiment 175:

[0484] The solvent dichloromethane in the fourth step of Example 149 was replaced by chloroform while keeping other conditions unchanged to obtain the product (Ia-6) in the same yield.

[0485] Embodiment 176:

[0486] The solvent dichloromethane in the fourth step of Example 149 was replaced with 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ia-6) in the same yield.

[0487] Embodiment 177:

[0488] The solvent dichloromethane in the fourth step of Example 149 was replaced by acetonitrile while keeping other conditions unchanged to obtain the product (Ia-6) in the same yield.

[0489] Embodiment 178:

[0490] By replacing the dichloromethane solvent in the fourth step of Example 149 with tetrahydrofuran and keeping other conditions unchanged, the product (Ia-6) was obtained in a slightly lower yield.

[0491] Embodiment 179:

[0492] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolinol (1.2 eq.) in a 25 mL round-bottom flask, add appropriate amounts of tert-butyl alcohol and anhydrous potassium carbonate (3 eq.), stir magnetically, and raise the temperature to about 90°C to allow it to fully reflux. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was completely detected by TLC, the reaction was terminated, the reaction was filtered, and the solvent was removed by vacuum rotary evaporation to obtain a crude product, which was separated and purified by column chromatography to obtain an o-nitroaniline intermediate; 3 molar equivalents of glacial acetic acid and zinc powder (slowly added), an appropriate amount of tetrahydrofuran was added, the temperature was lowered to 0°C, and magnetic stirring was performed. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was completely detected by TLC, the reaction was terminated, saturated sodium bicarbonate solution was added to quench, the pH was adjusted to alkaline, tetrahydrofuran was removed by vacuum rotary evaporation, appropriate amounts of water and dichloromethane were added for extraction, the aqueous phase was discarded, anhydrous sodium sulfate was added for washing, the product was filtered, dichloromethane was removed by vacuum rotary evaporation, and the product (II) was separated and purified by column chromatography; then the o-phenylenediamine intermediate was connected to a steric group through a condensation reaction, that is, the o-phenylenediamine intermediate (1 eq.) and 2-cyanobenzoic acid (1.2 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of dichloromethane was added. The reaction mixture was stirred overnight under magnetic stirring at room temperature until the reaction was complete as determined by TLC, and the aqueous solution was added and stirred for half an hour. An appropriate amount of water and dichloromethane were added for extraction. The aqueous phase was discarded, anhydrous sodium sulfate was added for washing, the mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The compound obtained by column chromatography was used for the next step of selective nitrogen oxidation reaction. An appropriate amount of dichloromethane was added as solvent to dissolve the raw materials. The reaction solution was cooled to 0°C, and an oxidant m-chloroperbenzoic acid (2.5 eq.) was added. The mixture was stirred for 8 to 10 hours under magnetic stirring. The reaction was completed as determined by TLC, and the reaction was terminated. A saturated sodium bicarbonate solution was added for quenching. The pH was adjusted to neutral. An appropriate amount of water and dichloromethane were added for extraction. The aqueous phase was discarded, anhydrous sodium sulfate was added for washing, the mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰa-7) was obtained by column chromatography.

[0493] The characterization data of (Ia-7) are as follows: mp: 115-130°C; 1H NMR (400MHz, Chloroform-d) δ15.11 (s, 1H), 8.18-8.12 (m, 1H), 8.02 (dd, J = 17.2, 7.4 Hz, 2H), 7.89 (td, J = 6.7, 6.1, 3.4 Hz, 2H), 7.56-7.49 (m, 1H), 7.32 (td, J = 5.0, 2.5 Hz, 2H), 7.28 (d, J = 1.9 Hz, 1H), 7.25-7. 18(m,2H),7.17–7.10(m,1H),7.08–6.98(m,2H),6.93–6.88(m,3H),6.82(t,J=7.6Hz,1H),5.55(dd,J= 9.0,6.7Hz,1H),4.18–3.94(m,1H),3.24(s,1H),2.81–2.65(m,1H),2.56(m,2H),1.87–1.72(m,2H).13C NMR(151MHz,Chloroform-d)δ161.14,148.52,134.10,132.26,128.43,128.38,127.39,125.58,124.69,1 23.40,122.97,121.86,121.78,119.46,109.55,85.42,78.40,42.79,29.71,26.06,23.47.HRMS(ESI)m / z calcd for C31H27N3O3Na+(M+Na)+512.1945,found 512.1946.

[0494] Embodiment 180:

[0495] The solvent of the first step in Example 179 was replaced by n-butanol with tert-butanol, and other conditions were the same to obtain the product (Ia-7) in the same yield.

[0496] Embodiment 181:

[0497] The solvent of the first step in Example 179 was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and the other conditions were the same. The product (Ia-7) was obtained in the same yield.

[0498] Embodiment 182:

[0499] The base anhydrous potassium carbonate in the first step of Example 179 was replaced with anhydrous sodium carbonate, and other conditions were the same to obtain the product (Ia-7) in the same yield.

[0500] Embodiment 183:

[0501] The base anhydrous potassium carbonate in the first step of Example 179 was replaced with anhydrous cesium carbonate, and other conditions were the same to obtain the product (Ia-7) in the same yield.

[0502] Embodiment 184:

[0503] The base anhydrous potassium carbonate in the first step of Example 179 was replaced by triethylamine, and the other conditions were the same to obtain the product (Ia-7) in the same yield.

[0504] Embodiment 185:

[0505] The solvent tetrahydrofuran in the second step of Example 179 was replaced with dichloromethane, and other conditions were the same to obtain the product (Ia-7) in a slightly higher yield.

[0506] Embodiment 186:

[0507] The solvent tetrahydrofuran in the second step of Example 179 was replaced with dioxane, and other conditions were the same to obtain the product (Ia-7) in the same yield.

[0508] Embodiment 187:

[0509] The solvent tetrahydrofuran in the second step of Example 179 was replaced with 1,2-dichloroethane, and other conditions were the same to obtain the product (Ia-7) in the same yield.

[0510] Embodiment 188:

[0511] The solvent tetrahydrofuran in the second step of Example 179 was replaced with acetonitrile, and other conditions were the same to obtain the product (Ia-7) in a slightly lower yield.

[0512] Embodiment 189:

[0513] The solvent tetrahydrofuran in the second step of Example 179 was replaced with anhydrous methanol, zinc powder was replaced with Raney nickel, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same to obtain the product (Ia-7) in a slightly higher yield.

[0514] Embodiment 190:

[0515] The solvent tetrahydrofuran in the second step of Example 179 was replaced with anhydrous methanol, zinc powder was replaced with Pd / C, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same to obtain the product (Ia-7) in a slightly lower yield.

[0516] Embodiment 191:

[0517] The zinc powder in the second step of Example 179 was replaced by iron powder, glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water system, and other conditions were the same to obtain the product (Ia-7) with a slightly lower yield.

[0518] Embodiment 192:

[0519] The zinc powder in the second step of Example 179 was replaced by tin dichloride, the glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water, the temperature was raised to 50°C, and other conditions remained unchanged to obtain the product (Ia-7) in a slightly lower yield.

[0520] Embodiment 193:

[0521] By replacing the dichloromethane solvent in the third step of Example 179 with acetonitrile and keeping other conditions unchanged, the product (Ia-7) was obtained in a slightly lower yield.

[0522] Embodiment 194:

[0523] The solvent dichloromethane in the third step of Example 179 was replaced with 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ia-7) in the same yield.

[0524] Embodiment 195:

[0525] The solvent dichloromethane in the third step of Example 179 was replaced by tetrahydrofuran, and the other conditions remained unchanged to obtain the product (Ia-7) in the same yield.

[0526] Embodiment 196:

[0527] The solvent dichloromethane in the third step of Example 179 was replaced with 1,2-dioxane while other conditions remained unchanged to obtain the product (Ia-7) in the same yield.

[0528] Embodiment 197:

[0529] The solvent dichloromethane in the third step of Example 179 was replaced by tetrahydrofuran, and the other conditions remained unchanged to obtain the product (Ia-7) in the same yield.

[0530] Embodiment 198:

[0531] The solvent dichloromethane in the third step of Example 179 was replaced by N,N-dimethylformamide while keeping other conditions unchanged to obtain the product (Ia-7) in the same yield.

[0532] Embodiment 199:

[0533] The condensation agent HATU in the third step of Example 179 was replaced by CDI, and nitrogen protection was used. The other conditions remained unchanged to obtain the product (Ia-7) in the same yield.

[0534] Embodiment 200:

[0535] The oxidant m-chloroperbenzoic acid in the fourth step of Example 179 was replaced by hydrogen peroxide, and the solvent was replaced by a methanol and water system. Other conditions remained unchanged, and the product (Ia-7) was obtained in the same yield.

[0536] Embodiment 201:

[0537] The oxidant m-chloroperbenzoic acid in the fourth step of Example 179 was replaced by hydrogen peroxide, and the solvent was replaced by an acetone and water system. Other conditions remained unchanged, and the product (Ia-7) was obtained in the same yield.

[0538] Embodiment 202:

[0539] The oxidant m-chloroperbenzoic acid in the fourth step of Example 179 was replaced by hydrogen peroxide, and the solvent was replaced by acetonitrile and water system. Other conditions remained unchanged, and the product (Ia-7) was obtained in the same yield.

[0540] Embodiment 203:

[0541] By replacing the oxidizing agent m-chloroperbenzoic acid in the fourth step of Example 179 with ruthenium trichloride and keeping other conditions unchanged, the product (Ia-7) was obtained in the same yield.

[0542] Embodiment 204:

[0543] Replace the oxidant m-chloroperbenzoic acid in the fourth step of Example 179 with ruthenium trichloride, and replace the solvent with 1,2-dichloroethane, while keeping other conditions unchanged, to obtain the product (Ia-7) in the same yield.

[0544] Embodiment 205:

[0545] The solvent dichloromethane in the fourth step of Example 179 was replaced by chloroform while keeping other conditions unchanged to obtain the product (Ia-7) in the same yield.

[0546] Embodiment 206:

[0547] The solvent dichloromethane in the fourth step of Example 179 was replaced with 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ia-7) in the same yield.

[0548] Embodiment 207:

[0549] The solvent dichloromethane in the fourth step of Example 179 was replaced by acetonitrile while keeping other conditions unchanged to obtain the product (Ia-7) in the same yield.

[0550] Embodiment 208:

[0551] By replacing the dichloromethane solvent in the fourth step of Example 179 with tetrahydrofuran and keeping other conditions unchanged, the product (Ia-7) was obtained in a slightly lower yield.

[0552] Embodiment 209:

[0553] Place o-fluoronitrobenzene (1 eq.) and (S)-α,α-diphenylprolinol (1.2 eq.) in a 25 mL round-bottom flask, add appropriate amounts of tert-butyl alcohol and anhydrous potassium carbonate (3 eq.), stir magnetically, and raise the temperature to about 90°C to allow it to fully reflux. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was completely detected by TLC, the reaction was terminated, the mixture was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, which was separated and purified by column chromatography to obtain an o-nitroaniline intermediate; 3 molar equivalents of glacial acetic acid and zinc powder (slowly added), an appropriate amount of tetrahydrofuran was added, the temperature was lowered to 0°C, and magnetic stirring was performed. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was completely detected by TLC, the reaction was terminated, saturated sodium bicarbonate solution was added to quench, the pH was adjusted to alkaline, tetrahydrofuran was removed by rotary evaporation under reduced pressure, appropriate amounts of water and dichloromethane were added for extraction, the aqueous phase was discarded, anhydrous sodium sulfate was added for washing, the mixture was filtered, dichloromethane was removed by rotary evaporation under reduced pressure, and product (II) was separated and purified by column chromatography; subsequently, the o-phenylenediamine intermediate was connected to a steric group through a condensation reaction, that is, the o-phenylenediamine intermediate (1 eq.) and 2-isopropylbenzoic acid (1.2 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of dichloromethane was added. The reaction mixture was stirred at room temperature overnight under magnetic stirring. The reaction was terminated by TLC after the reaction of the raw material was completely completed. An aqueous solution was added and stirred for half an hour. An appropriate amount of water and dichloromethane were added for extraction. The aqueous phase was discarded. Anhydrous sodium sulfate was added for washing. The mixture was filtered and dichloromethane was removed by rotary evaporation under reduced pressure. The compound obtained by column chromatography was used for the next step of selective nitrogen oxidation reaction. An appropriate amount of dichloromethane was added as a solvent to dissolve the raw material. The reaction solution was cooled to 0°C. An oxidant, m-chloroperbenzoic acid (2.5 eq.), was added and stirred under magnetic stirring for 8 to 10 hours. The reaction of the raw material was completely completed after TLC was detected. The reaction was terminated. A saturated sodium bicarbonate solution was added for quenching. The pH was adjusted to neutral. An appropriate amount of water and dichloromethane were added for extraction. The aqueous phase was discarded. Anhydrous sodium sulfate was added for washing. The mixture was filtered and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰa-8) was obtained by column chromatography.

[0554] The characterization data of (Ia-8) are as follows: mp: 110-125°C; 1H NMR (600MHz, Chloroform-d) δ14.28 (s, 1H), 9.66 (s, 1H), 8.61 (dd, J = 8.8, 1.6 Hz, 1H), 7.54-7.50 (m, 3H), 7.44-7.37 (m, 2H), 7.33-7.26 (m, 5H), 7.19-7.14 (m, 1H), 7.14-7.08 (m, 2H), 6.93 (ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 6.90-6.83 ( m,3H),5.30(t,J=8.8Hz,1H),4.00(td,J=11.3,7.2Hz,1H),3.89(dd,J=11.2,7.4Hz,1H),3.54(hept,J=6.9Hz,1H) ,2.70(m,1H),2.63–2.52(m,1H),2.20(m,1H),2.08–2.03(m,1H),1.36(d,J=6.8Hz,3H),1.26(d,J=6.9Hz,3H).13C NMR(151MHz,Chloroform-d)δ167.60,147.40,146.08,143.41,136.88,136.57,134.53,130.07,129.34,128.37,127.28,126.92,126.53(d,J =9.2Hz),126.30,125.89(d,J=3.4Hz),124.77,122.77,121.87,121.04,84.05,79.31,78.14,29.64,25.21,24.28,21.97.HRMS(ESI)m / zcalcd for C33H35N2O3+(M+H)+507.2642,found 507.2649.

[0555] Embodiment 210:

[0556] The solvent of the first step in Example 209 was replaced by n-butanol with tert-butanol, and other conditions were the same to obtain the product (Ia-8) in the same yield.

[0557] Example 211:

[0558] The solvent of the first step in Example 209 was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and the other conditions were the same to obtain the product (Ia-8) in the same yield.

[0559] Embodiment 212:

[0560] The product (Ia-8) was obtained in the same yield by replacing the base anhydrous potassium carbonate in the first step of Example 209 with anhydrous sodium carbonate and keeping the other conditions the same.

[0561] Embodiment 213:

[0562] The base anhydrous potassium carbonate in the first step of Example 209 was replaced with anhydrous cesium carbonate, and other conditions were the same to obtain the product (Ia-8) in the same yield.

[0563] Embodiment 214:

[0564] The base anhydrous potassium carbonate in the first step of Example 209 was replaced by triethylamine, and the other conditions were the same to obtain the product (Ia-8) in the same yield.

[0565] Embodiment 215:

[0566] The solvent tetrahydrofuran in the second step of Example 209 was replaced with dichloromethane, and other conditions were the same to obtain the product (Ia-8) in a slightly higher yield.

[0567] Example 216:

[0568] The solvent tetrahydrofuran in the second step of Example 209 was replaced with dioxane, and other conditions were the same to obtain the product (Ia-8) in the same yield.

[0569] Example 217:

[0570] The solvent tetrahydrofuran in the second step of Example 209 was replaced with 1,2-dichloroethane, and other conditions were the same to obtain the product (Ia-8) in the same yield.

[0571] Embodiment 218:

[0572] The solvent tetrahydrofuran in the second step of Example 209 was replaced with acetonitrile, and other conditions were the same to obtain the product (Ia-8) in a slightly lower yield.

[0573] Embodiment 219:

[0574] The solvent tetrahydrofuran in the second step of Example 209 was replaced with anhydrous methanol, zinc powder was replaced with Raney nickel, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same to obtain the product (Ia-8) in a slightly higher yield.

[0575] Example 220:

[0576] The solvent tetrahydrofuran in the second step of Example 209 was replaced with anhydrous methanol, zinc powder was replaced with Pd / C, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same to obtain the product (Ia-8) in a slightly lower yield.

[0577] Example 221:

[0578] The zinc powder in the second step of Example 209 was replaced by iron powder, glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water system, and other conditions were the same to obtain the product (Ia-8) with a slightly lower yield.

[0579] Example 222:

[0580] The zinc powder in the second step of Example 209 was replaced by tin dichloride, the glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water, the temperature was raised to 50°C, and other conditions remained unchanged to obtain the product (Ia-8) in a slightly lower yield.

[0581] Example 223:

[0582] By replacing the dichloromethane solvent in the third step of Example 209 with acetonitrile and keeping other conditions unchanged, the product (Ia-8) was obtained in a slightly lower yield.

[0583] Example 224:

[0584] The solvent dichloromethane in the third step of Example 209 was replaced with 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ia-8) in the same yield.

[0585] Example 225:

[0586] The solvent dichloromethane in the third step of Example 209 was replaced with tetrahydrofuran, and the other conditions remained unchanged to obtain the product (Ia-8) in the same yield.

[0587] Example 226:

[0588] The solvent dichloromethane in the third step of Example 209 was replaced with 1,2-dioxane while keeping other conditions unchanged to obtain the product (Ia-8) in the same yield.

[0589] Example 227:

[0590] The solvent dichloromethane in the third step of Example 209 was replaced with tetrahydrofuran, and the other conditions remained unchanged to obtain the product (Ia-8) in the same yield.

[0591] Example 228:

[0592] The solvent dichloromethane in the third step of Example 209 was replaced with N,N-dimethylformamide while keeping other conditions unchanged to obtain the product (Ia-8) in the same yield.

[0593] Example 229:

[0594] The condensation agent HATU in the third step of Example 209 was replaced by CDI, and nitrogen protection was used. The other conditions remained unchanged to obtain the product (Ia-8) in the same yield.

[0595] Embodiment 230:

[0596] The oxidant m-chloroperbenzoic acid in the fourth step of Example 209 was replaced by hydrogen peroxide, and the solvent was replaced by a methanol and water system. Other conditions remained unchanged, and the product (Ia-8) was obtained in the same yield.

[0597] Example 231:

[0598] The oxidant m-chloroperbenzoic acid in the fourth step of Example 209 was replaced by hydrogen peroxide, and the solvent was replaced by an acetone and water system. Other conditions remained unchanged, and the product (Ia-8) was obtained in the same yield.

[0599] Embodiment 232:

[0600] The oxidant m-chloroperbenzoic acid in the fourth step of Example 209 was replaced by hydrogen peroxide, and the solvent was replaced by acetonitrile and water system. Other conditions remained unchanged to obtain the product (Ia-8) in the same yield.

[0601] Embodiment 233:

[0602] By replacing the oxidizing agent m-chloroperbenzoic acid in the fourth step of Example 209 with ruthenium trichloride and keeping other conditions unchanged, the product (Ia-8) was obtained in the same yield.

[0603] Embodiment 234:

[0604] Replace the oxidant m-chloroperbenzoic acid in the fourth step of Example 209 with ruthenium trichloride, and replace the solvent with 1,2-dichloroethane, while keeping other conditions unchanged, and obtain the product (Ia-8) in the same yield.

[0605] Example 235:

[0606] The solvent dichloromethane in the fourth step of Example 209 was replaced by chloroform while keeping other conditions unchanged to obtain the product (Ia-8) in the same yield.

[0607] Example 236:

[0608] The solvent dichloromethane in the fourth step of Example 209 was replaced with 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ia-8) in the same yield.

[0609] Example 237:

[0610] The solvent dichloromethane in the fourth step of Example 209 was replaced by acetonitrile while keeping other conditions unchanged to obtain the product (Ia-8) in the same yield.

[0611] Embodiment 238:

[0612] By replacing the dichloromethane solvent in the fourth step of Example 209 with tetrahydrofuran and keeping other conditions unchanged, the product (Ia-8) was obtained in a slightly lower yield.

[0613] Embodiment 239:

[0614] Place o-fluoronitrobenzene (1 eq.) and (S)-2-benzhydrylpyrrolidine (1.2 eq.) in a 25 mL round-bottom flask, add appropriate amounts of tert-butyl alcohol and anhydrous potassium carbonate (3 eq.), stir magnetically, and heat to about 90°C to allow it to fully reflux. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was completely detected by TLC, the reaction was terminated, filtered, and the solvent was removed by vacuum rotary evaporation to obtain a crude product, which was separated and purified by column chromatography to obtain an o-nitroaniline intermediate; 3 molar equivalents of glacial acetic acid and zinc powder (slowly added), an appropriate amount of tetrahydrofuran was added, the temperature was lowered to 0°C, and magnetic stirring was performed. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was completely detected by TLC, the reaction was terminated, saturated sodium bicarbonate solution was added to quench, the pH was adjusted to alkaline, tetrahydrofuran was removed by vacuum rotary evaporation, appropriate amounts of water and dichloromethane were added for extraction, the aqueous phase was discarded, anhydrous sodium sulfate was added for washing, filtered, dichloromethane was removed by vacuum rotary evaporation, and product (II) was separated and purified by column chromatography; then the o-phenylenediamine intermediate was connected to a steric group through a condensation reaction, that is, the o-phenylenediamine intermediate (1 eq.) and 3,5-bis(trifluoromethyl)benzoic acid (1.2 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of Dichloromethane was used as solvent, HATU (1.5 eq.) was weighed as condensing agent, and magnetic stirring was carried out at room temperature overnight. The reaction of the raw material was detected by TLC to be completely reacted, and the reaction was terminated. An aqueous solution was added and stirred for half an hour, and appropriate amounts of water and dichloromethane were added for extraction. The aqueous phase was discarded, anhydrous sodium sulfate was added for washing, filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The compound obtained by column chromatography separation and purification was used for the next step of selective nitrogen oxidation reaction; an appropriate amount of dichloromethane was added as solvent to dissolve the raw material, the reaction solution was cooled to 0°C, and an oxidant m-chloroperbenzoic acid (2.5 eq.) was added, and magnetic stirring was carried out for 8 to 10 hours. The reaction of the raw material was detected by TLC to be completely reacted, and the reaction was terminated. A saturated sodium bicarbonate solution was added for quenching, the pH was adjusted to neutral, and appropriate amounts of water and dichloromethane were added for extraction. The aqueous phase was discarded, anhydrous sodium sulfate was added for washing, filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰb-1) was separated and purified by column chromatography.

[0615] The characterization data of (Ib-1) are: 1H NMR (600MHz, Chloroform-d) δ16.00 (s, 1H), 8.47–8.42 (m, 1H), 8.34 (d, J=1.7Hz, 2H), 7.96 (s, 1H), 7.23 (m, 1H), 7.17–7.11 (m, 3H), 7.09–7.06 (m, 2H), 7.01 (m, 1H), 6.98–6.94 (m, 2H) ,6.87–6.83(m,3H),6.81–6.76(m,1H),5.24(dt,J=9.0,6.9Hz,1H),4.30(td,J=10.3,7.3H z,1H),3.95(m,1H),3.64(d,J=9.1Hz,1H),2.57(m,1H),2.39(m,1H),1.98–1.85(m,2H).13C NMR(151MHz,Chloroform-d)δ161.31,141.30,140.01,137.66,137.06,134.39,132.11(d,J=11.0Hz),131.92,130.44,129.00,128.51,12 7.85(d,J=3.9Hz),127.30,127.14,126.45,125.22–124.80(m),122.83,122.52,120.56,87.48,71.25,54.38,28.72,20.86.HRMS(ESI)m / z calcd for C32H27F6N2O2+(M+H)+585.1971,found 585.1973.

[0616] Embodiment 240:

[0617] The product (Ib-1) was obtained in the same yield by replacing the solvent tert-butyl alcohol in the first step of Example 239 with n-butyl alcohol and keeping the other conditions the same.

[0618] Example 241:

[0619] The solvent of the first step in Example 239 was replaced by chloroform, the temperature was adjusted from 90°C to 50°C, and the other conditions were the same to obtain the product (Ib-1) in the same yield.

[0620] Example 242:

[0621] The product (Ib-1) was obtained in the same yield by replacing the base anhydrous potassium carbonate in the first step of Example 239 with anhydrous sodium carbonate and keeping the other conditions the same.

[0622] Example 243:

[0623] The product (Ib-1) was obtained in the same yield by replacing the base anhydrous potassium carbonate in the first step of Example 239 with anhydrous cesium carbonate and keeping the other conditions the same.

[0624] Example 244:

[0625] The product (Ib-1) was obtained in the same yield by replacing the base anhydrous potassium carbonate in the first step of Example 239 with triethylamine and keeping the other conditions the same.

[0626] Example 245:

[0627] The product (Ib-1) was obtained in a slightly higher yield by replacing the tetrahydrofuran solvent in the second step of Example 239 with dichloromethane and keeping the other conditions the same.

[0628] Example 246:

[0629] The product (Ib-1) was obtained in the same yield by replacing the tetrahydrofuran solvent in the second step of Example 239 with dioxane and keeping the other conditions the same.

[0630] Example 247:

[0631] The solvent tetrahydrofuran in the second step of Example 239 was replaced with 1,2-dichloroethane, and the other conditions were the same to obtain the product (Ib-1) in the same yield.

[0632] Example 248:

[0633] The product (Ib-1) was obtained in a slightly lower yield by replacing tetrahydrofuran as the solvent in the second step of Example 239 with acetonitrile and keeping the other conditions the same.

[0634] Example 249:

[0635] The solvent tetrahydrofuran in the second step of Example 239 was replaced with anhydrous methanol, zinc powder was replaced with Raney nickel, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same to obtain the product (Ib-1) in a slightly higher yield.

[0636] Embodiment 250:

[0637] The solvent tetrahydrofuran in the second step of Example 239 was replaced with anhydrous methanol, zinc powder was replaced with Pd / C, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same to obtain the product (Ib-1) in a slightly lower yield.

[0638] Example 251:

[0639] The zinc powder in the second step of Example 239 was replaced by iron powder, the glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water, and other conditions were the same to obtain the product (Ib-1) in a slightly lower yield.

[0640] Embodiment 252:

[0641] The zinc powder in the second step of Example 239 was replaced by tin dichloride, the glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water, the temperature was raised to 50°C, and other conditions remained unchanged to obtain the product (Ib-1) in a slightly lower yield.

[0642] Embodiment 253:

[0643] By replacing the dichloromethane solvent in the third step of Example 239 with acetonitrile and keeping other conditions unchanged, the product (Ib-1) was obtained in a slightly lower yield.

[0644] Example 254:

[0645] The solvent dichloromethane in the third step of Example 239 was replaced by 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ib-1) in the same yield.

[0646] Example 255:

[0647] The product (Ib-1) was obtained in the same yield by replacing the dichloromethane solvent in the third step of Example 239 with tetrahydrofuran and keeping other conditions unchanged.

[0648] Example 256:

[0649] The solvent dichloromethane in the third step of Example 239 was replaced with 1,2-dioxane while keeping other conditions unchanged to obtain the product (Ib-1) in the same yield.

[0650] Example 257:

[0651] The product (Ib-1) was obtained in the same yield by replacing the dichloromethane solvent in the third step of Example 239 with tetrahydrofuran and keeping other conditions unchanged.

[0652] Example 258:

[0653] The solvent dichloromethane in the third step of Example 239 was replaced by N,N-dimethylformamide while keeping other conditions unchanged to obtain the product (Ib-1) in the same yield.

[0654] Embodiment 259:

[0655] The condensing agent HATU in the third step of Example 239 was replaced by CDI, and the reaction mixture was protected by nitrogen. The other conditions remained unchanged, and the product (Ib-1) was obtained in the same yield.

[0656] Embodiment 260:

[0657] The product (Ib-1) was obtained in the same yield by replacing the oxidant m-chloroperbenzoic acid in the fourth step of Example 239 with hydrogen peroxide and the solvent with methanol and water system while keeping other conditions unchanged.

[0658] Example 261:

[0659] The product (Ib-1) was obtained in the same yield by replacing the oxidant m-chloroperbenzoic acid in the fourth step of Example 239 with hydrogen peroxide and the solvent with acetone and water system while keeping other conditions unchanged.

[0660] Example 262:

[0661] The product (Ib-1) was obtained in the same yield by replacing the oxidant m-chloroperbenzoic acid in the fourth step of Example 239 with hydrogen peroxide and the solvent with acetonitrile and water system while keeping other conditions unchanged.

[0662] Embodiment 263:

[0663] By replacing the oxidizing agent m-chloroperbenzoic acid in the fourth step of Example 239 with ruthenium trichloride and keeping other conditions unchanged, the product (Ib-1) was obtained in the same yield.

[0664] Example 264:

[0665] The product (Ib-1) was obtained in the same yield by replacing the oxidant m-chloroperbenzoic acid in the fourth step of Example 239 with ruthenium trichloride and the solvent with 1,2-dichloroethane while keeping other conditions unchanged.

[0666] Example 265:

[0667] The solvent dichloromethane in the fourth step of Example 239 was replaced by chloroform while keeping other conditions unchanged to obtain the product (Ib-1) in the same yield.

[0668] Example 266:

[0669] The solvent dichloromethane in the fourth step of Example 239 was replaced by 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ib-1) in the same yield.

[0670] Example 267:

[0671] The solvent dichloromethane in the fourth step of Example 239 was replaced by acetonitrile while keeping other conditions unchanged to obtain the product (Ib-1) in the same yield.

[0672] Example 268:

[0673] By replacing the dichloromethane solvent in the fourth step of Example 239 with tetrahydrofuran and keeping other conditions unchanged, the product (Ib-1) was obtained in a slightly lower yield.

[0674] Example 269:

[0675] Place o-fluoronitrobenzene (1 eq.) and (S)-2-benzhydrylpyrrolidine (1.2 eq.) in a 25 mL round-bottom flask, add appropriate amounts of tert-butyl alcohol and anhydrous potassium carbonate (3 eq.), stir magnetically, and heat to about 90°C to allow it to fully reflux. After 18 hours, the reaction of the raw material o-fluoronitrobenzene was completely detected by TLC, the reaction was terminated, the mixture was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, which was separated and purified by column chromatography to obtain an o-nitroaniline intermediate; 3 molar equivalents of glacial acetic acid and zinc powder (added slowly), an appropriate amount of tetrahydrofuran was added, the temperature was lowered to 0°C, and magnetic stirring was performed. After 12 hours, the reaction of the raw material o-nitroaniline intermediate was completely detected by TLC, the reaction was terminated, saturated sodium bicarbonate solution was added to quench, the pH was adjusted to alkaline, tetrahydrofuran was removed by rotary evaporation under reduced pressure, appropriate amounts of water and dichloromethane were added for extraction, the aqueous phase was discarded, anhydrous sodium sulfate was added for washing, the mixture was filtered, dichloromethane was removed by rotary evaporation under reduced pressure, and the product (II) was separated and purified by column chromatography; subsequently, the o-phenylenediamine intermediate was connected to a steric group through a condensation reaction, that is, the o-phenylenediamine intermediate (1 eq.) and benzofuran-2-carboxylic acid (1.2 eq.) were placed in a 25 mL round-bottom flask, and an appropriate amount of dichloromethane was added. Methane is used as solvent, HATU (1.5 eq.) is weighed as condensing agent, and magnetic stirring is carried out at room temperature overnight. The reaction of the raw material is detected by TLC to be completely reacted, and the reaction is terminated. An aqueous solution is added and stirred for half an hour, and appropriate amounts of water and dichloromethane are added for extraction. The aqueous phase is discarded, anhydrous sodium sulfate is added for washing, filtered, and dichloromethane is removed by rotary evaporation under reduced pressure. The compound obtained by column chromatography separation and purification is used for the next step of selective nitrogen oxidation reaction; an appropriate amount of dichloromethane is added as solvent to dissolve the raw material, the reaction solution is cooled to 0°C, and an oxidant m-chloroperbenzoic acid (2.5 eq.) is added, and magnetic stirring is carried out for 8 to 10 hours. The reaction of the raw material is detected by TLC to be completely reacted, and the reaction is terminated. A saturated sodium bicarbonate solution is added for quenching, the pH is adjusted to neutral, and appropriate amounts of water and dichloromethane are added for extraction. The aqueous phase is discarded, anhydrous sodium sulfate is added for washing, filtered, and dichloromethane is removed by rotary evaporation under reduced pressure. The target chiral nitrogen oxide (NO) compound (Ⅰb-2) is separated and purified by column chromatography.

[0676] The characterization data of (Ib-2) are as follows: mp: 122-135°C; 1H NMR (400MHz, Chloroform-d) δ15.38 (s, 1H), 8.47 (dd, J = 8.7, 1.5 Hz, 1H), 7.73 (t, J = 8.1 Hz, 2H), 7.54 (s, 1H), 7.47 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.32-7.12 (m, 5H), 7.12 –7.06(m,2H),7.03(td,J=7.8,1.6Hz,1H),7.00–6.89(m,5H),5.44(td,J=7.6,4.3Hz,1H),4.37 (q,J=9.6Hz,1H),3.93(m,1H),3.74(d,J=8.9Hz,1H),2.79–2.64(m,2H),2.14–2.00(m,2H).13C NMR(101MHz,Chloroform-d)δ156.41,155.37,150.03,141.26,139.85,136.62,134.78,130.19,128.95,128.51(d,J=8.7Hz),127.78,127 .22,127.04,126.70,126.43,123.55,122.95,122.54,122.07,120.08,112.56,110.07,86.36,68.87,54.86,28.04,20.66.HRMS(ESI)m / z calcd for C32H29N2O3+(M+H)+489.2173,found 489.2174.

[0677] Embodiment 270:

[0678] The product (Ib-2) was obtained in the same yield by replacing the solvent tert-butanol in the first step of Example 269 with n-butanol and keeping the other conditions the same.

[0679] Example 271:

[0680] The solvent of the first step in Example 269 was replaced with chloroform, the temperature was adjusted from 90°C to 50°C, and the other conditions were the same to obtain the product (Ib-2) in the same yield.

[0681] Example 272:

[0682] The product (Ib-2) was obtained in the same yield by replacing the base anhydrous potassium carbonate in the first step of Example 269 with anhydrous sodium carbonate and keeping the other conditions the same.

[0683] Embodiment 273:

[0684] The product (Ib-2) was obtained in the same yield by replacing the base anhydrous potassium carbonate in the first step of Example 269 with anhydrous cesium carbonate and keeping the other conditions the same.

[0685] Example 274:

[0686] The product (Ib-2) was obtained in the same yield by replacing the base anhydrous potassium carbonate in the first step of Example 269 with triethylamine and keeping the other conditions the same.

[0687] Example 275:

[0688] The product (Ib-2) was obtained in a slightly higher yield by replacing the tetrahydrofuran solvent in the second step of Example 269 with dichloromethane and keeping the other conditions the same.

[0689] Example 276:

[0690] The product (Ib-2) was obtained in the same yield by replacing the tetrahydrofuran solvent in the second step of Example 269 with dioxane and keeping the other conditions the same.

[0691] Example 277:

[0692] The solvent tetrahydrofuran in the second step of Example 269 was replaced with 1,2-dichloroethane, and other conditions were the same to obtain the product (Ib-2) in the same yield.

[0693] Embodiment 278:

[0694] The solvent tetrahydrofuran in the second step of Example 269 was replaced with acetonitrile, and the other conditions were the same to obtain the product (Ib-2) in a slightly lower yield.

[0695] Embodiment 279:

[0696] The solvent tetrahydrofuran in the second step of Example 269 was replaced with anhydrous methanol, zinc powder was replaced with Raney nickel, glacial acetic acid was replaced with H2, and the pressure was increased, while other conditions were the same to obtain the product (Ib-2) in a slightly higher yield.

[0697] Embodiment 280:

[0698] The solvent tetrahydrofuran in the second step of Example 269 was replaced by anhydrous methanol, zinc powder was replaced by Pd / C, glacial acetic acid was replaced by H2, and the pressure was increased while other conditions were the same to obtain the product (Ib-2) in a slightly lower yield.

[0699] Example 281:

[0700] The zinc powder in the second step of Example 269 was replaced by iron powder, the glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water, and the other conditions were the same to obtain the product (Ib-2) in a slightly lower yield.

[0701] Embodiment 282:

[0702] The zinc powder in the second step of Example 269 was replaced by tin dichloride, the glacial acetic acid was replaced by dilute hydrochloric acid, the solvent was replaced by water, the temperature was raised to 50°C, and other conditions remained unchanged to obtain the product (Ib-2) in a slightly lower yield.

[0703] Embodiment 283:

[0704] By replacing the dichloromethane solvent in the third step of Example 269 with acetonitrile and keeping other conditions unchanged, the product (Ib-2) was obtained in a slightly lower yield.

[0705] Embodiment 284:

[0706] The solvent dichloromethane in the third step of Example 269 was replaced by 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ib-2) in the same yield.

[0707] Example 285:

[0708] The product (Ib-2) was obtained in the same yield by replacing the solvent dichloromethane in the third step of Example 269 with tetrahydrofuran and keeping other conditions unchanged.

[0709] Example 286:

[0710] The solvent dichloromethane in the third step of Example 269 was replaced with 1,2-dioxane while other conditions remained unchanged to obtain the product (Ib-2) in the same yield.

[0711] Example 287:

[0712] The product (Ib-2) was obtained in the same yield by replacing the solvent dichloromethane in the third step of Example 269 with tetrahydrofuran and keeping other conditions unchanged.

[0713] Embodiment 288:

[0714] The solvent dichloromethane in the third step of Example 269 was replaced by N,N-dimethylformamide while keeping other conditions unchanged to obtain the product (Ib-2) in the same yield.

[0715] Embodiment 289:

[0716] The condensing agent HATU in the third step of Example 269 was replaced by CDI, and nitrogen protection was used. The other conditions remained unchanged to obtain the product (Ib-2) in the same yield.

[0717] Embodiment 290:

[0718] The product (Ib-2) was obtained in the same yield by replacing the oxidant m-chloroperbenzoic acid in the fourth step of Example 269 with hydrogen peroxide and the solvent with methanol and water system while keeping other conditions unchanged.

[0719] Example 291:

[0720] The product (Ib-2) was obtained in the same yield by replacing the oxidant m-chloroperbenzoic acid in the fourth step of Example 269 with hydrogen peroxide and the solvent with acetone and water system while keeping other conditions unchanged.

[0721] Embodiment 292:

[0722] The product (Ib-2) was obtained in the same yield by replacing the oxidant m-chloroperbenzoic acid in the fourth step of Example 269 with hydrogen peroxide and the solvent with acetonitrile and water system while keeping other conditions unchanged.

[0723] Embodiment 293:

[0724] By replacing the oxidizing agent m-chloroperbenzoic acid in the fourth step of Example 269 with ruthenium trichloride and keeping other conditions unchanged, the product (Ib-2) was obtained in the same yield.

[0725] Embodiment 294:

[0726] The product (Ib-2) was obtained in the same yield by replacing the oxidant m-chloroperbenzoic acid in the fourth step of Example 269 with ruthenium trichloride and the solvent with 1,2-dichloroethane while keeping other conditions unchanged.

[0727] Example 295:

[0728] The solvent dichloromethane in the fourth step of Example 269 was replaced by chloroform while keeping other conditions unchanged to obtain the product (Ib-2) in the same yield.

[0729] Example 296:

[0730] The solvent dichloromethane in the fourth step of Example 269 was replaced by 1,2-dichloroethane while keeping other conditions unchanged to obtain the product (Ib-2) in the same yield.

[0731] Example 297:

[0732] The solvent dichloromethane in the fourth step of Example 269 was replaced by acetonitrile while keeping other conditions unchanged to obtain the product (Ib-2) in the same yield.

[0733] Embodiment 298:

[0734] By replacing the dichloromethane solvent in the fourth step of Example 269 with tetrahydrofuran and keeping other conditions unchanged, the product (Ib-2) was obtained in a slightly lower yield.

[0735] The above examples are merely illustrative of the present invention and do not constitute a limitation on the protection scope of the present invention. All designs that are the same or similar to the present invention fall within the protection scope of the present invention.

Claims

1. A general method for generating axial chirality through a chiral association strategy, the characteristics and concept of which are as follows: Substituent Rb is not the same as Rs Rb, Rs substituent groups: functional groups with specific functions that can participate in the formation of coordination bonds, hydrogen bonds, etc. Chiral aromatic tertiary amine compounds without nitrogen chiral centers induce the generation of new aromatic tertiary amine nitrogen oxide (NO) chiral centers through intramolecular chiral oxidation. Due to the structural rigidity of chiral aromatic tertiary amine nitrogen oxide compounds, when the steric hindrance of different substituent groups Rb and Rs connected to the ortho position of the aromatic ring is large, their rotation is hindered, and new rotationally hindered axial chirality is generated simultaneously with the formation of the aromatic tertiary amine chiral nitrogen oxide center.

2. The general method for generating axial chirality by chiral association strategy as claimed in claim 1, by regulating the structure and functional properties of different substituent groups Rb and Rs, and by different combinations of groups Rb, Rs and BG, various types of axial chiral ligands and chiral small molecule catalysts can be prepared. Typically, R b and R s Different commonly used coordination substituent groups or coordination atoms, including but not limited to R, Ar, -NHR 20 , -OH, -CN, -CHO, -COOR 21 , The steric hindering group BG and the chiral source include but are not limited to In the formula, R* is a chiral source, Ar is a substituted or unsubstituted C6-C50 aryl, aryl, condensed aryl, substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 aralkyloxy, substituted or unsubstituted C7-C50 aralkylthiol, substituted or unsubstituted C7-C50 aromatic heterocyclic group, substituted or unsubstituted C7-C30 aromatic amine, aromatic heterocyclic group, etc., R, R a , R c , R d , R f , R p , R q , R u , R v , R 2a , R 2b , R 2c , R 2u , R 3a , R 3b , R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 Each is independently selected from a hydrogen atom, a C1-C30 alkyl group, a C1-C30 silyl group, a C1-C30 haloalkyl group, a C2-C30 alkenyl group, a C2-C30 alkynyl group, a halogen, a hydroxyl group, an alkoxy group, an acyloxy group, a thiol group, a thioether group, a nitro group, a carbonyl group, a carboxyl group, an ester group, an amino group and a substituted amino group, an imino group, a cyano group, an amide group, a phosphoamido group, a sulfonamide group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group, and an electron-withdrawing or or an electron donating protecting group or an arbitrary substituent; it may also be selected from a substituted or unsubstituted C6-C50 aryl, a fused aryl, a substituted or unsubstituted C7-C50 aralkyl, a substituted or unsubstituted C7-C50 aralkyloxy, a substituted or unsubstituted C7-C50 aralkylthiol, a substituted or unsubstituted C7-C50 aromatic heterocyclic group, a substituted or unsubstituted C7-C30 aromatic amine, an aromatic heterocyclic group, a fused heterocyclic group, and a fused heterocyclic group.

3. An axially chiral aromatic tertiary amine nitrogen oxide ligand compound, characterized in that: Based on the method described in claim 2, the substituent Rb or Rs can be widely selected from different types of ligands or their structural combinations, and can form a bidentate or multidentate chiral ligand together with the chiral nitrogen oxide compound; the ligand includes but is not limited to: oxygen ligands, nitrogen ligands, sulfur ligands, double bond ligands, sulfoxide ligands, nitrile ligands, sulfonamides, phosphamides, amide ligands, ureas, thioureas, oxazoline ligands, imidazoline ligands, thiazoline ligands, pyrazoles, triazoles, tetrazoles, pyrazoline, pyrroles, indoles and other heterocyclic ligands.

4. The axially chiral aromatic tertiary amine nitrogen-oxygen ligand compound according to claim 2 and claim 3, characterized in that: By combining different nitrogen-oxygen chiral sources with different ligands, chiral compounds of different types and functions are obtained; the axial chiral aromatic tertiary amine nitrogen-oxygen ligand compounds include but are not limited to: o-(p-methylbenzenesulfonamide) diphenyl (hydroxy) prolinol nitrogen-oxygen compounds, o-(methylsulfonamide) diphenyl (hydroxy) prolinol nitrogen-oxygen compounds, o-(p-nitrobenzenesulfonamide) diphenyl (hydroxy) prolinol nitrogen-oxygen compounds, o-(carbonitrile) diphenyl (hydroxy) prolinol nitrogen-oxygen compounds, o-(benzaldehyde) diphenyl (hydroxy) prolinol nitrogen-oxygen compounds, o-(olefin) diphenyl (hydroxy) prolinol nitrogen-oxygen compounds, o-(ester) diphenyl (hydroxy) prolinol nitrogen-oxygen compounds, o-(amide) diphenyl (hydroxy) prolinol nitrogen-oxygen compounds, o-(urea) Diphenyl (hydroxy) prolinol nitrogen oxides, o-(thiourea) diphenyl (hydroxy) prolinol nitrogen oxides, o-(oxazoline) diphenyl (hydroxy) prolinol nitrogen oxides, o-(imidazole) diphenyl (hydroxy) prolinol nitrogen oxides, o-(benzimidazole) diphenyl (hydroxy) prolinol nitrogen oxides, o-(thiazole) diphenyl (hydroxy) prolinol nitrogen oxides, o-(benzothiazole) diphenyl (hydroxy) prolinol nitrogen oxides, o-(triazole) diphenyl (hydroxy) prolinol nitrogen oxides, o-(tetrazolyl) diphenyl (hydroxy) prolinol nitrogen oxides, o-(p-methylbenzenesulfonamide) (hydroxy) prolinamide nitrogen oxides, o-(methylsulfonamide) (hydroxy) prolinamide nitrogen oxides, o-(p-nitrophenyl) Benzenesulfonamide)(hydroxy)prolineamide nitrogen oxides, o-(carbonitrile)(hydroxy)prolineamide nitrogen oxides, o-(benzaldehyde)(hydroxy)prolineamide nitrogen oxides, o-(olefin)(hydroxy)prolineamide nitrogen oxides, o-(ester)(hydroxy)prolineamide nitrogen oxides, o-(amide)(hydroxy)prolineamide nitrogen oxides, o-(urea)(hydroxy)prolineamide nitrogen oxides, o-(thiourea)(hydroxy)prolineamide nitrogen oxides, o-(oxazoline)(hydroxy)prolineamide nitrogen oxides, o-(imidazole)(hydroxy)prolineamide nitrogen oxides, o-(benzimidazole)(hydroxy)prolineamide nitrogen oxides, o-(thiazole)(hydroxy)prolineamide nitrogen oxides, o-(benzothiazole)(hydroxy ) prolineamide nitrogen oxides, o-(triazole) (hydroxy) prolineamide nitrogen oxides, o-(tetrazolyl) (hydroxy) prolineamide nitrogen oxides, o-(p-methylbenzenesulfonamide) (hydroxy) proline oxazoline nitrogen oxides, o-(methylsulfonamide) (hydroxy) proline oxazoline nitrogen oxides, o-(p-nitrobenzenesulfonamide) (hydroxy) proline oxazoline nitrogen oxides, o-(carbonitrile) (hydroxy) proline oxazoline nitrogen oxides, o-(benzaldehyde) (hydroxy) proline oxazoline nitrogen oxides, o-(olefin) (hydroxy) proline oxazoline nitrogen oxides, o-(ester) (hydroxy) proline oxazoline nitrogen oxides, o-(amide) (hydroxy) proline oxazoline nitrogen oxides, o-(urea) (hydroxy) proline oxazoline nitrogen oxides,o-(thiourea) (hydroxy) prolyl oxazoline nitrogen oxides, o-(oxazoline) (hydroxy) prolyl oxazoline nitrogen oxides, o-(imidazole) (hydroxy) prolyl oxazoline nitrogen oxides, o-(benzimidazole) (hydroxy) prolyl oxazoline nitrogen oxides, o-(thiazole) (hydroxy) prolyl oxazoline nitrogen oxides, o-(benzothiazole) (hydroxy) prolyl oxazoline nitrogen oxides, o-(triazole) (hydroxy) prolyl oxazoline nitrogen oxides, o-(tetrazolyl) (hydroxy) prolyl oxazoline nitrogen oxides; The structure of the axial chiral aromatic tertiary amine nitrogen oxide ligand compound is shown below: In the formula, Y is selected from H and O; Z is selected from O and N; X 1 Selected from O, S; X 2 , X 4 Selected from O, S; X 3 Selected from C, P; X 5 Selected from H, O, N; R c , R d , R f , R 1 , R 2 , R 4 , R 5 , R 6 , R 7a , R 8a , R 11 , R 12 , R 13 , R 14 , R 21 , R 22 , R 23 , R 24 , R 25 , R 28a , R 29a , R 33 , R 34 , R 35 , R 36 , R 37 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 Each is independently selected from a hydrogen atom, a C1-C30 alkyl group, a C1-C30 silyl group, a C1-C30 haloalkyl group, a C2-C30 alkenyl group, a C2-C30 alkynyl group, a halogen, a hydroxyl group, an alkoxy group, an acyloxy group, a thiol group, a thioether group, a nitro group, a carbonyl group, a carboxyl group, an ester group, an amino group and a substituted amino group, an imino group, a cyano group, an amide group, a phosphoamido group, a sulfonamide group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group, and an electron-withdrawing or or an electron donating protecting group or an arbitrary substituent; or one selected from substituted or unsubstituted C6-C50 aryl, aryl and fused aryl, substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 aralkyloxy, substituted or unsubstituted C7-C50 aralkylthiol, substituted or unsubstituted C7-C50 aromatic heterocyclic group, substituted or unsubstituted C7-C30 aromatic amine, arbitrary aromatic heterocyclic group, aryl heterocyclic group and fused heterocyclic group.

5. The axially chiral aromatic tertiary amine nitrogen oxide ligand compound according to claim 4, characterized in that: It has the potential to be used as a small molecule chiral catalyst and chiral ligand, and can catalyze different types of asymmetric reactions; the axial chiral aromatic tertiary amine nitrogen oxide ligand compound includes but is not limited to: Where: Y 1 Selected from C, N; X 6 Selected from O, S, NR 14 ; R 2u , R 2c , R 3c , R 5 , R 6 , R 7a , R 8a , R 14 , R 36 , R 37 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 Each is independently selected from a hydrogen atom, a C1-C30 alkyl group, a C1-C30 silyl group, a C1-C30 haloalkyl group, a C2-C30 alkenyl group, a C2-C30 alkynyl group, a halogen, a hydroxyl group, an alkoxy group, an acyloxy group, a thiol group, a thioether group, a nitro group, a carbonyl group, a carboxyl group, an ester group, an amino group and a substituted amino group, an imino group, a cyano group, an amide group, a phosphoamido group, a sulfonamide group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group, and an electron-withdrawing or or an electron donating protecting group or an arbitrary substituent; or one selected from substituted or unsubstituted C6-C50 aryl, aryl and fused aryl, substituted or unsubstituted C7-C50 aralkyl, substituted or unsubstituted C7-C50 aralkyloxy, substituted or unsubstituted C7-C50 aralkylthiol, substituted or unsubstituted C7-C50 aromatic heterocyclic group, substituted or unsubstituted C7-C30 aromatic amine, arbitrary aromatic heterocyclic group, aryl heterocyclic group and fused heterocyclic group.

6. A method for preparing an aromatic tertiary amine nitrogen-oxygen axial chiral ligand compound, which can be prepared by the following representative synthetic route:

7. The method for preparing an aromatic tertiary amine nitrogen-oxygen axial chiral ligand compound as claimed in claim 6, characterized in that: The reaction steps are as follows: (1) Using o-fluoronitrobenzene as the starting material, under the action of temperature T1, solvent S1, and base B1, a chiral prolinol compound C1 is reacted with the chiral prolinol compound C1 to form a S-type prolinol. N Ar2 reaction, followed by nitro reduction, to form an ortho-aryl chiral diamine compound of formula II; The solvent S1 includes one or more of alcohol, halogenated hydrocarbon and ether solvents; the base B1 includes one or more of inorganic base and organic base; the reaction temperature T1 is 25°C to 100°C; (2) Under the conditions of temperature T4, solvent S4 and oxidant O1, the target aromatic tertiary amine nitrogen-oxygen axial chiral ligand compound represented by formula I is obtained by selective nitrogen oxidation of the chiral tertiary amine; The oxidant O1 includes meta-chloroperbenzoic acid, peracetic acid, peroxyacetic acid, hydrogen peroxide, and ruthenium trichloride; the solvent S4 includes one or more of halogenated hydrocarbons, ethers, and nitrile solvents; and the reaction temperature T4 is -78°C to 20°C.

8. The method for preparing an aromatic tertiary amine nitrogen-oxygen axial chiral ligand compound according to any one of claims 6 or 7, characterized in that: The synthetic route can be used as a chiral phase transfer catalyst to catalyze different types of asymmetric reactions, and can also be used as a precursor or synthon of medicines, pesticides or bioactive compounds, because the key intermediate chiral tertiary amine can further form a chiral quaternary ammonium salt.

9. The use of the axially chiral aromatic tertiary amine nitrogen oxide ligand compound according to any one of claims 3 to 5, characterized in that: Through the structural and functional regulation of the aromatic substituent groups adjacent to the nitrogen-oxygen chiral center, the axially chiral aromatic tertiary amine nitrogen-oxygen (NO) coordination atom, together with the coordination group Rs or Rb, acts as a bidentate or multidentate chiral ligand to coordinate with a variety of central metals to catalyze different types of asymmetric reactions.

10. The use according to claim 9, characterized in that: Due to the dipole characteristics of chiral nitrogen oxides, they have significant nucleophilicity and Lewis basicity. The oxygen atom can act as an electron pair donor to form molecular adducts or complexes with Lewis acidic compounds. They can be widely used as new Lewis bases or small molecule chiral catalysts, chiral reverse phase transfer catalysts, etc. in the fields of asymmetric catalysis, chiral synthesis, chiral resolution, and chiral substances.

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